Progress 03/04/19 to 03/03/24
Outputs
PROGRESS REPORT Objectives (from AD-416): We will: 1)study the effect of enteral nutrition on the downstream signaling pathways and metabolism;2)study if increased FGF19 availability controls rate of growth, tissue protein synthesis and intestinal development;3)study if being born prematurely blunts protein and glucose metabolic responses to the feeding-induced rise in amino acids and insulin; 4)identify by which amino acids, regulate protein synthesis, degradation, and accretion and how responses change with age;5)removed due to investigator departure;6)study molecular mechanisms and functional significance of differences in gene expression identified in satellite cell-derived myoblasts;7)study the impact of maternal dietary protein level during lactation;8)study if vitamin D receptors in the brain are critical for glucose regulation;9)study if leptin is involved in the regulation of gluconeogenesis via the leptin receptor and if leptin agonist and small doses of hypoglycin-A/B reduces gluconeogenesis;10) study the role of the SIRT3 in regulation of pyruvate carboxylase and the gluconeogenesis pathway;11)alter DNA methylation in specific subpopulations of hypothalamic neurons and evaluate lifelong effects on energy metabolism, food intake, and PA;12)find the causes of interindividual epigenetic variation and consequences for human energy balance;13)study the functional impact of folic acid supplementation and in intestinal carcinogenesis;14)study the effect of adiposity, adipokine dysregulation, insulin resistance and vitamin D concentrations on bone and endothelial function; 15)study the effect of vitamin D therapy on change in bone and endothelial function;16)removed due to investigator departure;17)study the CNS circuit architecture and explore circuit complexities that regulate non-homeostatic feeding behaviors via environmental signals transduced by epigenetic mechanisms;18)study the tumorigenic effects of HFCS on a humanized colon tumor mouse model;19) study the effects of HFCS on the gut microbiota of a humanized colon tumor mouse model;20)study the role of HFCS-induced gut microbiota in CRC development; create multi-omic nutritional data share portal to resolve the unmet demand for an efficient access to the large volumes of heterogeneous multi-omic data across various research labs;21)integrate heterogeneous multi-omic datasets such as genetic (SNPs), transcriptomic, epigenetic, proteomic, metabolomic and microbiome to infer molecular network structures illustrating eating disorder dynamics;&22)decode genetic and epigenetic patterns of disordered eating using machine learning methods. Approach (from AD-416): This research will be accomplished using a variety of models and scientific tools to simulate the human newborn and/or child. Researchers will use neonatal piglet and rodent models to fill these knowledge gaps. We will determine whether being born prematurely blunts the anabolic response to feeding and identify mechanisms by which amino acids, particularly leucine, regulate lean growth. Additionally we will use various rodent models to test leptin's effect on gluconeogenesis that is independent of body weight, and will utilize in vitro experiments employing primary hepatocytes. Scientists will also integrate both detailed studies of animal models and characterization of epigenetic mechanisms in humans. We will use mouse models of developmental epigenetics in the hypothalamus to understand cell type-specific epigenetic mechanisms mediating developmental programming of body weight regulation. Mouse models will also be used to investigate how folic acid intake affects epigenetic mechanisms regulating intestinal epithelial stem cell (IESC) development and characterize the involvement of these mechanisms in metabolic programming related to obesity, inflammation, and gastrointestinal cancer. In human studies, we will identify human genomic loci at which interindividual variation in DNA methylation is both sensitive to maternal nutrition in early pregnancy and associated with risk of later weight gain. We will also examine whether restoration of vitamin D sufficiency, in a randomized placebo controlled study design, has a positive effect on bone microarchitecture, bone biomarkers and endothelial function. Studies will be conducted in mice that will uncover the molecular basis of interrelationships among dietary sugar, gut microbiota, and CRC development and identify sugar-induced metabolites and/or microbes that can serve as new biomarkers and targets. Researchers will also conduct a multi-omic integrative study to systematically decipher the molecular interplay of disordered eating and neuron specific brain circuits that control feeding behavior. To review the progress made during the year, please refer to the following projects: 3092-10700-070-010S (Project #1), 3092-10700-070-020S (Project #2), 3092-10700-070-030S (Project #3) and 3092-10700-070-040S (Project #4). Artificial Intelligence (AI)/Machine Learning (ML) We employed advanced Artificial Intelligence (AI) and Machine Learning (ML) methods, specifically deep learning models, to address complex biological problems related to RNA processing. For the tool PolyAMiner- Bulk, we developed a deep learning-based algorithm using an attention- based BERT model to decode alternative polyadenylation (APA) dynamics from bulk RNA-seq data. This model treated RNA sequences as a language, capturing intricate dependencies to accurately infer APA dynamics. The training of this model was conducted on a local high-performance server equipped with an A30 GPU, 64 processing cores, 512 GB of RAM, and 50TB of hard disk space. Similarly, to decode cryptic splicing, we utilized machine learning models to study how pathogenic variants affect cryptic splicing repression. These models were also trained and tested on the same local high-performance server. This infrastructure and the use of AI and ML methods has dramatically increased the accuracy and efficiency of our data processing, allowing for more precise analysis and interpretation of complex RNA-seq data. This has, in turn, enabled us to make significant advancements in understanding gene regulation mechanisms and their impact on diseases, particularly in the context of metabolic diseases, pediatric nutrition and obesity research. ACCOMPLISHMENTS 01 How premature birth impacts infant nutrition and growth. In the United States, a substantial number of infants are born prematurely, leading to reduced capacity to digest, absorb, and metabolize nutrients essential for healthy growth and development. Researchers at the Children's Nutrition Research Center in Houston, Texas, used infant pigs as a model for human infants to investigate how premature birth adversely impacts metabolism and growth. We revealed that premature birth results in a reduced secretion of cortisol, a key stress hormone normally released near full-term birth. This diminished cortisol level is linked to a decreased production of hepatic bile and reduced intestinal secretion of the hormone fibroblast growth factor 19 (FGF19). This immaturity in bile metabolism may explain why premature infants have difficulty digesting fat, a critical source of nutrition for their growth and development. This finding may elucidate why the therapeutic use of stress hormones, often administered to hospitalized premature infants to induce lung development, may also improve their overall nutrient metabolism and growth. 02 Targeted nutritional therapy can overcome the anabolic resistance of preterm birth. Preterm infants gain less body weight than full-term infants due to reduced muscle growth, but not fat accumulation. This contributes to long-term adverse health outcomes, such as obesity and type 2 diabetes. Research at the Children's Nutrition Research Center in Houston, Texas, showed the synthesis of protein in skeletal muscle after a meal is lower in preterm pigs than in those that are born at full term. They also showed that supplementing formula with the amino acid leucine, which targets key cell signaling pathways, can overcome this anabolic resistance in preterm muscle. These studies provide vital information on the mechanisms underlying reduced muscle growth in preterm infants and may lead to targeted nutritional therapies to improve lean growth in premature infants. 03 Youth-onset type 2 diabetes is not suppressed by a combination therapy of metformin and liraglutide. Youth-onset type 2 diabetes is a rapidly progressive disease characterized by increased glucose production from the liver, rapid failure of pancreatic cells (B-cell) that produce insulin, and severe insulin resistance. This chronic disease is magnified among African American youth who have the highest disease prevalence and burden of metabolic complications. Since increased rates of glucose production from the liver is an important primary factor in youth-onset type 2 diabetes, researchers at the Children's Nutrition Research Center in Houston, Texas, investigated the effectiveness of a combination therapy of metformin with a glucagon like peptide-1 receptor agonist (liraglutide), in reducing glucose production from the liver and improving B-cell function. We showed that youth-onset type 2 diabetes is associated with dysregulated and high rates of glucose production from the liver which were not suppressed by metformin alone or in combination with liraglutide. Increased glucose clearance was related to improvements in B-cell function. These findings show that early combination therapies that will abrogate multiple pathways that contribute to high rates of glucose production and improve B-cell function in youth-onset type 2 diabetes are needed. 04 Obesity-associated glycine deficiency impairs the human detoxification system which can be improved when glycine supply is restored. Glycine is an amino acid that is central to human metabolism, is integral of the human detoxification system, and is required in large amounts by the human body. Plasma glycine concentration is low in individuals with severe obesity and is associated with impaired glycine synthesis. Interestingly, both glycine synthesis and glycine levels improve after bariatric surgery. Researchers at the Children's Nutrition Research Center in Houston, Texas, examined the impact of obesity-associated glycine deficiency and bariatric surgery on the detoxification system in humans. We showed that obesity-associated glycine deficiency impairs the human detoxification system, and this impairment is improved when glycine supply is restored after bariatric surgery. This finding proposes that dietary glycine supplementation could treat obesity- associated metabolic complications due to the accumulation of toxic metabolites by helping the body get rid of harmful substances more efficiently. 05 High dietary vitamin D protects aging mice against blood sugar abnormalities only in males. Vitamin D is important for health but there are conflicting results on its impact in humans. Most research does not analyze sex-specific effects of vitamin D, although some data exists that vitamin D may only be protective against diabetes in males. Researchers at the Children's Nutrition Research Center in Houston, Texas, found that middle-aged mice on high vitamin D levels had improved blood sugar levels compared to those on normal or low vitamin D diets. This may be secondary to differences in gene expression of important glucose-regulating proteins in the liver; males on a high vitamin D diet had higher expression levels of the insulin receptor but no effect of diet was seen in the females. These findings give evidence that males and females may respond to vitamin D differently and support human studies showing that vitamin D, as currently administered, may only be beneficial for glucose control in males. Future research is needed to determine how to improve female response to dietary vitamin D. 06 Dietary folate enhances colon cancer risk in animal models. There is an unresolved debate about the extent to which the environment contributes to cancer risk. Although epidemiological studies suggest that environmental factors such as diet can certainly contribute to this risk, especially for colon cancer, how dietary factors could tip the scale in favor of cancer is not known. Researchers at the Children's Nutrition Research Center in Houston, Texas, developed the first mouse model of engineered p16 promoter hypermethylation, leading to accelerated p16 epimutation in somatic tissues during aging. This work investigates the link between age-related p16 epimutation which is regulated by folate and intestinal tumorigenesis, identifying potential targets for colorectal cancer treatment. It also sheds light on the connection between diet and epigenetic regulation in cancer development. Importantly, these findings highlight the need to monitor the long- term safety of folate fortification in high-risk individuals. 07 Discovering novel splicing changes with new software. Novel splicing events in genes, called cryptic splicing events, are often missed by traditional tools but are crucial for understanding the biological phenomenon. To address this gap, specialized computational tools are necessary to accurately identify cryptic splicing. Researchers at the Children's Nutrition Research Center in Houston, Texas, developed a new software that finds these hidden changes and shows how diet affects them, offering new ways to manage metabolic diseases like diabetes. Researchers have used this tool to uncover genetic changes in heart failure and mental health disorders, leading to new diagnostic markers and treatments influenced by diet. This work broadens our understanding of gene regulation and its nutritional impacts, benefiting public health. By identifying diet-related splicing changes, the software opens avenues for personalized nutrition plans to prevent and treat metabolic conditions including obesity and diabetes. 08 The effect of cold on body fat and health. Brown fat helps keep us warm by burning energy, and cold temperatures make it more active. Researchers at the Children's Nutrition Research Center in Houston, Texas, studied the effect of temperature on body fat and health by housing mice at different temperatures, from comfortable to very cold and profiling their molecular changes. We saw a decrease in DNA methylation and increases in certain protein modifications, which together aid in regulating how brown fat genes turn on or off to produce heat in response to cold. This discovery suggests new ways to treat obesity and diabetes by understanding body heat and energy use and could lead to treatments that mimic cold effects on brown fat. This research impacts how we manage body fat and energy and highlights the potential for environmental and lifestyle changes to play a significant role in combating metabolic diseases. 09 Sexual dimorphism in the relationship of obesity and dysglycemia with bone microarchitecture in youth. In adults, individuals with type 2 diabetes are known to have worse bone quality and a higher risk of fractures. The relationship between obesity, type 2 diabetes and bone health in youth however is unclear and this is important since the majority of bone formation occurs during the adolescent years. Researchers at the Children's Nutrition Research Center in Houston, Texas, examined the relationship of adiposity and glucose metabolism to bone quality and strength measures in adolescents with obesity, with and without type 2 diabetes, and compared with their normal weight counterparts. We found that bone mineral content, quality, and strength measures were worse in boys with abnormalities in their glucose compared with obesity but normal glucose than those who are of normal weight. The negative effects of high blood sugar on bone health may be more evident in adolescent boys than in girls and additional studies are needed to better understand what factors may explain the effect.
Impacts
(N/A)
Publications
- Pham, D.T., Westerman, K.E., Pan, C., Chen, L., Srinivasan, S., Isganaitis, E., Vajravelu, M., Bacha, F., Chernausek, S., Gubitosi-Klug, R., Divers, J., Pihoker, C., Marcovina, S.M., Manning, A.K., Chen, H. 2023. Re- analysis and meta-analysis of summary statistics from gene-environment interaction studies. Bioinformatics. 39(12). Article btad730. https://doi. org/10.1093/bioinformatics/btad730.
- Bacha, F., El-Ayash, H., Mohamad, M., Sharma, S., Puyau, M., Kanchi, R., Coarfa, C. 2024. Distinct amino acid profile characterizes youth with or at risk for type 2 diabetes. Diabetes. 73(4):628⿿636. https://doi.org/10. 2337/db23-0375.
- Koren, D., Knutson, K.L., Burke, B.K., Drews, K.L., Bacha, F., Katz, L., Marcus, M.D., McKay, S., Nadeau, K., Mokhlesi, B., and on behalf of the TODAY Study Group. 2024. The association of self-reported sleep and circadian measures with glycemic control and diabetes complications among young adults with type 2 diabetes: Results from the TODAY2 study. American Journal of Physiology - Heart and Circulatory Physiology. 326(6) :H1386⿿H1395. https://doi.org/10.1152/ajpheart.00550.2023.
- Jonnakuti, V.S., Wagner, E.J., Maletic-Savatic, M., Liu, Z., Yalamanchili, H.K. 2024. PolyAMiner-Bulk is a deep learning-based algorithm that decodes alternative polyadenylation dynamics from bulk RNA-seq data. Cell Reports Methods. 4. Article 100707. https://doi.org/10.1016/j.crmeth.2024.100707.
- Khan, M., Chen, X.X., Dias, M., Santos, J.R., Kour, S., You, J., Van Bruggen, R., Youssef, M.M., Wan, Y., Liu, Z., Rosenfeld, J.A., Tan, Q., Pandey, U.B., Yalamanchili, H.K., Park, J. 2024. MATR3 pathogenic variants differentially impair its cryptic splicing repression function. FEBS Letters. 598:415-436. https://doi.org/10.1002/1873-3468.14806.
- Chadchan, S.B., Popli, P., Liao, Z., Andreas, E., Dias, M., Wang, T., Gunderson, S.J., Jimenez, P.T., Lanza, D.G., Lanz, R.B., Foulds, C.E., Monsivais, D., Demayo, F.J., Yalamanchili, H.K., Jungheim, E.S., Heaney, J. D., Lydon, J.P., Moley, K.H., O'Malley, B.W., Kommagani, R. 2024. A GREB1- steroid receptor feedforward mechanism governs differential GREB1 action in endometrial function and endometriosis. Nature Communications. 15. Article 1947. https://doi.org/10.1038/s41467-024-46180-4.
- Taylor, B.C., Steinthal, L.H., Dias, M., Yalamanchili, H.K., Ochsner, S.A., Zapata, G.E., Mehta, N.R., McKenna, N.J., Young, N.L., Nuotio-Antar, A.M. 2024. Histone proteoform analysis reveals epigenetic changes in adult mouse brown adipose tissue in response to cold stress. Epigenetics and Chromatin. 17. Article 12. https://doi.org/10.1186/s13072-024-00536-8.
- Elefson, S.K., Stoll, B., Davis, T., Fiorotto, M.L., El Kadi, S.W., Genovese, K.J., Thymann, T., Sangild, P.T., Burrin, D.G. 2024. Adverse metabolic phenotypes in parenterally fed neonatal pigs do not persist into adolescence. Journal of Nutrition. 154(2):638-647. https://doi.org/10.1016/ j.tjnut.2023.12.048.
- Maj, M.A., Burrin, D.G., Manjarin, R. 2023. Decreased FXR agonism in the bile acid pool is associated with impaired FXR signaling in a pig model of pediatric NAFLD. Biomedicines. 11(12). Article 3303. https://doi.org/10. 3390/biomedicines11123303.
- Foster, K.L., Lee, D.J., Witchel, S.F., Gordon, C.M. 2024. Ovarian insufficiency and fertility preservation during and after childhood cancer treatment. Journal of Adolescent and Young Adult Oncology. https://doi.org/ 10.1089/jayao.2023.0111.
- Posey, E.A., Davis, T.A. 2023. Review: Nutritional regulation of muscle growth in the neonatal swine. Animal-The International Journal of Animal Biosciences. 17(3). Article 100831. https://doi.org/10.1016/j.animal.2023. 100831.
- Rudar, M., Suryawan, A., Nguyen, H.V., Chacko, S.K., Vonderohe, C., Stoll, B., Burrin, D.G., Fiorotto, M.L., Davis, T.A. 2023. Pulsatile leucine administration during continuous enteral feeding enhances skeletal muscle mechanistic target of rapamycin complex 1 signaling and protein synthesis in a preterm piglet model. Journal of Nutrition. 154(2):505⿿515. https:// doi.org/10.1016/j.tjnut.2023.12.034.
- Suryawan, A., Rudar, M., Naberhuis, J.K., Fiorotto, M.L., Davis, T.A. 2022. Preterm birth alters the feeding-induced activation of Akt signaling in the muscle of neonatal piglets. Pediatric Research. 93(7):1891-1898. https://doi.org/10.1038/s41390-022-02382-4.
- Chang, W., Baker, M.S., Laritsky, E., Gunasekara, C.J., Maduranga, U., Galliou, J.C., McFadden, J.W., Waltemyer, J.R., Berggren-Thomas, B., Tate, B.N., Zhang, H., Rosen, B.D., Van-Tassell, C.P., Liu, G.E., Coarfa, C., Ren, Y., Waterland, R.A. 2024. Systemic interindividual DNA methylation variants in cattle share major hallmarks with those in humans. Genome Biology. 25. Article 185. https://doi.org/10.1186/s13059-024-03307-6.
- Rasmussen, M., Holgersen, K., Pankratova, S., Baek, O., Burrin, D.G., Thymann, T., Sangild, P. 2023. Gut development following insulin-like growth factor-1 supplementation to preterm pigs. Pediatric Research. 95:1528-1535. https://doi.org/10.1038/s41390-023-02949-9.
- Yang, L., Peery, R.C., Farmer, L.M., Gao, X., Zhang, Y., Creighton, C.J., Zhang, L., Shen, L. 2024. Dietary folate and cofactors accelerate age- dependent p16 epimutation to promote intestinal tumorigenesis. Cancer Research Communications. 4(1):164⿿169. https://doi.org/10.1158/2767-9764. CRC-23-0356.
- Dietsche, K.B., Magge, S.N., Dixon, S.A., Davis, F.S., Krenek, A., Chowdhury, A., Mabundo, L., Stagliano, M., Courville, A.B., Yang, S., Turner, S., Cai, H., Kasturi, K., Sherman, A.S., Ha, J., Shouppe, E., Walter, M., Walter, P.J., Chen, K.Y., Brychta, R.J., Peer, C., Zeng, Y., Figg, W., Cogen, F., Estrada, D., Chacko, S., Chung, S.T. 2023. Glycemia and gluconeogenesis with metformin and liraglutide: A randomized trial in youth-onset type 2 diabetes. Journal of Clinical Endocrinology and Metabolism. https://doi.org/10.1210/clinem/dgad669.
- Yang, L., Peery, R.C., Farmer, L.M., Gao, X., Zhang, Y., Creighton, C.J., Zhang, L., Shen, L. 2024. Dietary folate and cofactors accelerate age- dependent p16 epimutation to promote intestinal tumorigenesis. Cancer Research Communications. 4(1):164-169. https://doi.org/10.1158/2767-9764. CRC-23-0356.
- Rudar, M., Naberhuis, J.K., Suryawan, A., Nguyen, H.V., Fiorotto, M.L., Davis, T.A. 2023. Prematurity blunts protein synthesis in skeletal muscle independently of body weight in neonatal pigs. Pediatric Research. 94(1) :143-152. https://www.nature.com/articles/s41390-022-02456-3.
- Quaye, E., Chacko, S., Startzell, M., Brown, R.J. 2023. Leptin decreases gluconeogenesis and gluconeogenic substrate availability in patients with lipodystrophy. Journal of Clinical Endocrinology and Metabolism. 109(1) :e209-e215. https://doi.org/10.1210/clinem/dgad445.
- Tang, H., Hsu, J.W., Tai, E., Chacko, S., Kovalik, J., Jahoor, F. 2024. The impact of obesity-associated glycine deficiency on the elimination of endogenous and exogenous metabolites via the glycine conjugation pathway. Frontiers in Endocrinology. 15. Article 1343738. https://doi.org/10.3389/ fendo.2024.1343738.
- The RADIANT Study Group. 2023. The Rare and Atypical Diabetes Network (RADIANT) study: Design and early results. Diabetes Care. 46(6):1265-1270. https://doi.org/10.2337/dc22-2440.
- Wasserman, H., Jenkins, T., Inge, T., Ryder, J., Michalsky, M., Sisley, S., Xie, C., Kalkwarf, H.J. 2024. Bone mineral density in young adults 5 to 11 years after adolescent metabolic and bariatric surgery for severe obesity compared to peers. International Journal of Obesity. 48:575-583. https://doi.org/10.1038/s41366-023-01453-8.
- Baumert, B.O., Fischer, F.C., Nielsen, F., Grandjean, P., Bartell, S., Stratakis, N., Walker, D., Valvi, D., Kohli, R., Inge, T., Ryder, J., Jenkins, T., Sisley, S., Xanthakos, S., Rock, S., La Merrill, M.A., Conti, D., McConnell, R., Chatzi, L. 2023. Paired liver: Plasma PFAS concentration ratios from adolescents in the teen-LABS study and derivation of empirical and mass balance models to predict and explain liver PFAS accumulation. Environmental Science and Technology. 57:14817- 14826. https://doi.org/10.1021/acs.est.3c02765.
- Kubota-Mishra, E., Huang, X., Minard, C.G., Astudillo, M., Refaey, A., Montes, G., Sisley, S., Ram, N., Winter, W.E., Naylor, R.N., Balasubramanyam, A., Redondo, M.J., Tosur, M., and RADIANT Study Group. 2024. High prevalence of A-B+ ketosis-prone diabetes in children with type 2 diabetes and diabetic ketoacidosis at diagnosis: Evidence from the Rare and Atypical Diabetes Network (RADIANT). Pediatric Diabetes. Article 5907924. https://doi.org/10.1155/2024/5907924.
- Baumert, B.O., Eckel, S.P., Goodrich, J.A., Li, Z., Stratakis, N., Walker, D.I., Zhao, Y., Fischer, F.C., Bartell, S., Valvi, D., Lin, X., Fuentes, Z. C., Inge, T., Ryder, J., Jenkins, T., Kohli, R., Sisley, S., Xanthakos, S., Rock, S., La Merrill, M.A., McConnell, R., Conti, D.V., Chatzi, L. 2024. Changes in plasma concentrations of per- and polyfluoroalkyl substances after bariatric surgery in adolescents from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study. Science of the Total Environment. 930. Article 172840. https://doi.org/10.1016/j.scitotenv.2024. 172840.
- Rubbo, B., Li, Z., Tachachartvanich, P., Baumert, B.O., Wang, H., Pan, S., Rock, S., Ryder, J.R., Jenkins, T., Sisley, S., Lin, X., Bartell, S., Inge, T.H., Xanthakos, S., McNeil, B., Robuck, A.R., La Merrill, M.A., Walker, D.I., Conti, D.V., McConnell, R., Eckel, S.P., Chatzi, L. 2024. Exposure to 4,4'-DDE in visceral adipose tissue and weight loss in adolescents from the Teen-LABS cohort. Obesity. 32(5):1023-1032. https://doi.org/10.1002/ oby.24009.
- Li, Y., Baumert, B.O., Stratakis, N., Goodrich, J.A., Wu, H., He, J., Zhao, Y., Aung, M.T., Wang, H., Eckel, S.P., Walker, D.I., Valvi, D., La Merrill, M.A., Ryder, J.R., Inge, T.H., Jenkins, T., Sisley, S., Kohli, R., Xanthakos, S., Baccarelli, A.A., McConnell, R., Conti, D.V., Chatzi, L. 2024. Circulating microRNA expression and nonalcoholic fatty liver disease in adolescents with severe obesity. World Journal of Gastroenterology. 30(4):332-345. https://doi.org/10.3748/wjg.v30.i4.332.
- Sanyal, S., Calarge, C., Rowan, P.J., Aparasu, R.R., Abughosh, S., Sisley, S., Chen, H. 2023. Adherence to recommended metabolic monitoring of children and adolescents taking second-generation antipsychotics. Psychiatric Services. 75(4):342-348. https://doi.org/10.1176/appi.ps. 20220584.
- Garcia Castro, D.R., Mazuk, J.R., Heine, E.M., Simpson, D., Pinches, R., Lozzi, C., Hoffman, K., Morrin, P., Mathis, D., Lebedev, M.V., Nissley, E., Hoo Han, K., Farmer, T., Merry, D.E., Tong, Q., Pennuto, M., Montie, H.L. 2023. Increased SIRT3 combined with PARP inhibition rescues motor function of SBMA mice. iScience. 26(3). Article 107375. https://doi.org/10.1016/j. isci.2023.107375.
- Bacha, F., Gupta, R., Jenkins, T.M., Brandt, M.L., Inge, T.H., Kleiner, D. E., Xanthakos, S.A., for the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) Consortium. 2024. Prognostic factors in resolution of nonalcoholic fatty liver disease post bariatric surgery in adolescents. Elsevier. 20(4):367-375. https://doi.org/10.1016/j.soard.2023.11.004.
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Progress 10/01/22 to 09/30/23
Outputs
PROGRESS REPORT Objectives (from AD-416): We will: 1)study the effect of enteral nutrition on the downstream signaling pathways and metabolism;2)study if increased FGF19 availability controls rate of growth, tissue protein synthesis and intestinal development;3)study if being born prematurely blunts protein and glucose metabolic responses to the feeding-induced rise in amino acids and insulin; 4)identify by which amino acids, regulate protein synthesis, degradation, and accretion and how responses change with age;5)removed due to investigator departure;6)study molecular mechanisms and functional significance of differences in gene expression identified in satellite cell-derived myoblasts;7)study the impact of maternal dietary protein level during lactation;8)study if vitamin D receptors in the brain are critical for glucose regulation;9)study if leptin is involved in the regulation of gluconeogenesis via the leptin receptor and if leptin agonist and small doses of hypoglycin-A/B reduces gluconeogenesis;10) study the role of the SIRT3 in regulation of pyruvate carboxylase and the gluconeogenesis pathway;11)alter DNA methylation in specific subpopulations of hypothalamic neurons and evaluate lifelong effects on energy metabolism, food intake, and PA;12)find the causes of interindividual epigenetic variation and consequences for human energy balance;13)study the functional impact of folic acid supplementation and in intestinal carcinogenesis;14)study the effect of adiposity, adipokine dysregulation, insulin resistance and vitamin D concentrations on bone and endothelial function; 15)study the effect of vitamin D therapy on change in bone and endothelial function;16)removed due to investigator departure;17)study the CNS circuit architecture and explore circuit complexities that regulate non-homeostatic feeding behaviors via environmental signals transduced by epigenetic mechanisms;18)study the tumorigenic effects of HFCS on a humanized colon tumor mouse model;19) study the effects of HFCS on the gut microbiota of a humanized colon tumor mouse model;20)study the role of HFCS-induced gut microbiota in CRC development; create multi-omic nutritional data share portal to resolve the unmet demand for an efficient access to the large volumes of heterogeneous multi-omic data across various research labs;21)integrate heterogeneous multi-omic datasets such as genetic (SNPs), transcriptomic, epigenetic, proteomic, metabolomic and microbiome to infer molecular network structures illustrating eating disorder dynamics;&22)decode genetic and epigenetic patterns of disordered eating using machine learning methods. Approach (from AD-416): This research will be accomplished using a variety of models and scientific tools to simulate the human newborn and/or child. Researchers will use neonatal piglet and rodent models to fill these knowledge gaps. We will determine whether being born prematurely blunts the anabolic response to feeding and identify mechanisms by which amino acids, particularly leucine, regulate lean growth. Additionally we will use various rodent models to test leptin's effect on gluconeogenesis that is independent of body weight, and will utilize in vitro experiments employing primary hepatocytes. Scientists will also integrate both detailed studies of animal models and characterization of epigenetic mechanisms in humans. We will use mouse models of developmental epigenetics in the hypothalamus to understand cell type-specific epigenetic mechanisms mediating developmental programming of body weight regulation. Mouse models will also be used to investigate how folic acid intake affects epigenetic mechanisms regulating intestinal epithelial stem cell (IESC) development and characterize the involvement of these mechanisms in metabolic programming related to obesity, inflammation, and gastrointestinal cancer. In human studies, we will identify human genomic loci at which interindividual variation in DNA methylation is both sensitive to maternal nutrition in early pregnancy and associated with risk of later weight gain. We will also examine whether restoration of vitamin D sufficiency, in a randomized placebo controlled study design, has a positive effect on bone microarchitecture, bone biomarkers and endothelial function. Studies will be conducted in mice that will uncover the molecular basis of interrelationships among dietary sugar, gut microbiota, and CRC development and identify sugar-induced metabolites and/or microbes that can serve as new biomarkers and targets. Researchers will also conduct a multi-omic integrative study to systematically decipher the molecular interplay of disordered eating and neuron specific brain circuits that control feeding behavior. To review the progress made during the year, please refer to the following projects: 3092-51000-065-01S (Project #1), 3092-51000-065-02S (Project #2), 3092-51000-065-03S (Project #3) and 3092-51000-065-04S (Project #4). ACCOMPLISHMENTS 01 Researchers discover trouble in the epigenetics toolbox. Epigenetics describes the molecular mechanisms that enable our different cell types to develop and stably maintain different structures and functions. For more than a decade, researchers worldwide have been performing population studies to detect associations between DNA methylation (the most stable epigenetic mark) and disease; and nearly all these studies have used the same commercial methylation arrays. Scientists at the Children's Nutrition Research Center (CNRC) in Houston, Texas, reported that these arrays are not appropriate for population epigenetics, because 95% of the genomic sites they target do not show appreciable interindividual variation among humans (without interindividual variation, detecting associations is impossible). Additionally, we validated an innovative approach for studying Correlated Regions of Systemic Interindividual epigenetic Variation (CoRSIVs, which CNRC scientists discovered in 2019) and demonstrated the superiority of targeting CoRSIVs by documenting over 70-fold more genetic influence on human DNA methylation than had been previously documented. These advances call into question the results of over 1,000 studies of population epigenetics conducted over the last decade. A new product being marketed makes this technology available to epigenetic epidemiologists worldwide, helping the field of science to move forward. 02 A robust and integrative database framework to quickly find and use/ integrate heterogeneous data. Investigating the complexities of nutrition benefits and rare diseases is akin to piecing together an intricate jigsaw puzzle and each fragment of this puzzle represents information gathered from a multitude of research studies. Despite numerous analytical standards, datasets, and tools, the scientific community often struggles to efficiently comprehend these vast data sources. To address these challenges, researchers at the Children's Nutrition Research Center in Houston, Texas, have developed an integrative database framework that meticulously organizes scientific information, including gene expression profiles. A significant problem we successfully tackled is the issue of "batch effects," which can introduce potential biases when integrating evidence from different scientists; our framework allows us to identify and account for these effects, enabling the discovery of recurring patterns in gene behaviors that individual studies might miss due to their limited scope. In essence, our newfound approach empowers scientists to gain a more comprehensive understanding of specific nutrients or diseases by examining a wide range of data. Our methodology offers a more efficient pathway for the scientific community to explore critical biological questions, ultimately benefiting farmers and consumers with precise dietary recommendations and nutritional planning. 03 Stress hormone promotes gut development in preterm pigs. Bile production is critical for fat digestion in newborn infants. Researchers at the Children's Nutrition Research Center in Houston, Texas have discovered that a stress hormone regulates the production of a novel gut hormone, Fibroblast Growth Factor 19 (FGF19) that is important in controlling the amount of bile made in the liver. Preterm piglets were used as a model for human infants to show that prematurity reduces the secretion of FGF19. The findings show that vaginal birth and production of the stress hormone, cortisol, during labor strongly stimulate the production of FGF19 in the blood. Treatment of intestinal cells with this stress hormone induce secretion of FGF19. Glucocorticoids, like cortisol, are frequently given to expectant preterm mothers and their newborn infants after birth to accelerate lung maturation. This finding points to cortisol treatment as a potential opportunity to also regulate FGF19, which may be valuable to improve growth, metabolic and hepatic outcomes in preterm babies. These findings are exciting because they could be an important step toward improved neonate care, particularly preterm neonates 04 Parent struggles in caring for children with severe obesity. Parents of children under five years of age with severe obesity must implement lifestyle changes at different developmental stages for potentially long periods of time. Since little data exists on the experiences of these parents as they care for their children, researchers at the Children's Nutrition Research Center in Houston, Texas, performed interviews with parents of children having early-onset obesity. Researchers found that mothers struggled with frequent blaming by their friends, family, and many medical professionals and felt unheard by the medical community. Mothers were also highly motivated to protect their child⿿s self-esteem, even from perceived damage by doctors, nurses, and dietitians. These results are important as they convey the great effort mothers are making in caring for their children and point to a great need by the medical community to provide individualized and compassionate care to obese children and their families. 05 Metreleptin treatment reduces gluconeogenesis in patients with lipodystrophy. Lipodystrophy is a rare disease characterized by deficiencies of adipose tissue and the hormone leptin, resulting in metabolic derangements akin to obesity-associated metabolic syndrome. Individuals with lipodystrophy are treated with a synthetic analog of leptin (metreleptin) to improve blood sugar (glucose) control and decreases energy expenditure. Scientists at the Children's Nutrition Research Center in Houston, Texas, demonstrated that metreleptin treatment in those with lipodystrophy reduced glucose production in the liver, likely through the decreased availability of carbon sources typically found in proteins. Additionally, scientists showed that metroleptin improved insulin sensitivity and markers of glucose control. Our findings provide insights for future research to find effective treatments for leptin deficient conditions. The data from our study supports the role of protein breakdown in insulin resistance conditions and suggests that therapeutic interventions targeting protein breakdown may improve blood sugar control. 06 Increased circulatory non-hydroxylated bile acids are associated with increased insulin sensitivity in humans. Bile acids are steroid acids that are produced in the liver and there is substantial data linking bile acids to obesity and diabetes risk. Insulin resistance is a condition when cells do not respond efficiently to insulin and are unable to easily take up glucose from the blood. Insulin resistance has been shown to be associated with an increased concentration of certain hydroxylated bile acids. Scientists at the Children's Nutrition Research Center in Houston, Texas, showed that different genetic mutations in humans was associated with an increase in non-hydroxylated bile acids and increased insulin sensitivity. This finding related to bile acids serves as a potential novel target for future therapeutic intervention for diabetes. 07 Glycine synthesis is reduced in adults with morbid obesity and increases following bariatric surgery. Insulin resistance is a condition when cells in muscles, fat, and liver do not respond efficiently to insulin and are unable to easily take up glucose from blood. Obesity is a risk factor for insulin resistance and is associated with disturbances in the metabolism of not only glucose and lipids, but also of certain amino acids. Scientists at the Children⿿s Nutrition Research Center in Houston, Texas, demonstrated that low plasma glycine concentration in humans with severe obesity and insulin resistance is associated with impaired glycine synthesis, which is improved after bariatric surgery. This finding implies that glycine may be a conditionally essential amino acid in obesity. Additionally, it has important human implications since plasma glycine concentrations can be raised by simple measures such as dietary supplementation 08 Acanthosis nigricans predicts low vitamin D levels in children. Vitamin D deficiency can cause significant health problems, including the bone disease rickets; yet guidelines differ on when children should be screened for vitamin D deficiency. Acanthosis nigricans, a darkening of skin around the neck, correlates with low vitamin D levels in predominantly white children but it was unknown if acanthosis nigricans could be used as a clinical sign to predict low vitamin D levels in children with darker skin tones (like Hispanic or Black children). Researchers at the Children's Nutrition Research Center in Houston, Texas, found that low vitamin D levels were 3.6 times more likely in minority children with acanthosis nigricans. This research further supports that children with acanthosis nigricans should have vitamin D levels checked routinely as they may be more at risk of vitamin D deficiency.
Impacts
(N/A)
Publications
- Vonderohe, C., Guthrie, G., Stoll, B., Melendez Hebib, V., Dawson, H.D., Burrin, D.G. 2022. Increased circulating cortisol after vaginal birth is associated with increased FGF19 secretion in neonatal pigs. Endocrinology. 164(1). https://doi.org/10.1210/endocr/bqac188.
- Perez, K., Valentine, G.C., Nangia, S., Burrin, D.G., Maheshwari, A., Abayneh, M., Workneh, R., Jerome, M., Dinerstein, A., Salas, A. 2022. Advancement of enteral feeding in very-low-birth-weight infants: Global issues and challenges. Newborn. https://doi.org/10.5005/jp-journals-11002- 0038.
- Lin, S., Wang, S., Wang, P., Tang, C., Wang, Z., Chen, L., Luo, G., Chen, H., Liu, Y., Feng, B., Wu, D., Burrin, D.G., Fang, Z. 2022. Bile acids and their receptors in regulation of gut health and diseases. Progress in Lipid Research. 89. Article 101210. https://doi.org/10.1016/j.plipres.2022. 101210.
- Gunasekara, C., MacKay, H., Scott, C., Li, S., Laritsky, E., Baker, M., Grimm, S.L., Jun, G., Li, Y., Chen, R., Wiemels, J.L., Coarfa, C., Waterland, R.A. 2023. Systemic interindividual epigenetic variation in humans is associated with transposable elements and under strong genetic control. Genome Biology. 24. Article 2. https://doi.org/10.1186/s13059-022- 02827-3.
- Melendez Hebib, V., Taft, D., Stoll, B., Liu, J., Call, L., Guthrie, G., Jensen, N., Hair, A.B., Mills, D.A., Burrin, D.G. 2023. Probiotics and human milk differentially influence the gut microbiome and NEC incidence in preterm pigs. Gut Microbes. 15(11):2585. https://doi.org/10.3390/ nu15112585.
- Ismail, H.M., Barua, S., Wang, J., Sabharwal, A., Libman, I., Bacha, F., Nadeau, K.J., Tosur, M., Redondo, M.J. 2023. Baseline leptin predicts response to metformin in adolescents with type 1 diabetes and increased body mass index. Diabetes Obesity and Metabolism. https://doi.org/10.1111/ dom.15218.
- Rudar, M., Suryawan, A., Nguyen, H.V., Chacko, S.K., Vonderohe, C., Stoll, B., Burrin, D.G., Fiorotto, M.L., Davis, T.A. 2023. Regulation of skeletal muscle protein synthesis in the preterm pig by intermittent leucine pulses during continuous parenteral feeding. American Society for Parenteral and Enteral Nutrition. https://doi.org/10.1002/jpen.2450.
- Rambout, X., Cho, H., Blanc, R., Lyu, Q., Miano, J.M., Chakkalakal, J.V., Nelson, G.M., Yalamanchili, H.K., Adelman, K., Maquat, L.E. 2023. PGC- 1alpha senses the CBC of pre-mRNA to dictate the fate of promoter- proximally paused RNAPII. Molecular Cell. 83(2):186-202. https://doi.org/ 10.1016/j.molcel.2022.12.022.
- Zhong, S., Chevre, R., Castano Mayan, D., Corliano, M., Cochran, B.J., Ping Sem, K., Van Dijik, T.H., Peng, J., Juin Tan, L., Hartimath, S.V., Ramasamy, B., Cheng, P., Groen, A.K., Kuipers, F., Goggi, J.L., Drum, C., Van Dam, R.M., San Tan, R., Rye, K., Hayden, M.R., Cheng, C., Chacko, S., Flannick, J., Sim, X., Chang Tan, H., Singaraja, R.R. 2022. Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans. Journal of Clinical Investigation. 132(21). Article e152961. https://doi.org/10.1172/JCI152961.
- Nadeau, K.J., El Ghormli, L., Arslanian, S., Bacha, F., Caprio, S., Chan, C., Chao, L.C., Rayas, M., Siska, M.K., Zeitler, P. 2023. Effect of early glycemic control in youth-onset type 2 diabetes on longer-term glycemic control and b-cell function: Results from the TODAY Study. Diabetes Care. 46(8):1507-1514. https://doi.org/10.2337/dc23-0560.
- Jonnakuti, V.S., Ji, P., Gao, Y., Lin, A., Chu, Y., Elrod, N., Huang, K., Li, W., Yalamanchili, H.K., Wagner, E.J. 2023. NUDT21 alters glioma migration through differential alternative polyadenylation of LAMC1. Journal of Neuro-Oncology. https://doi.org/10.1007/s11060-023-04370-y.
- Tan, H.C., Hsu, J.W., Tai, E., Chacko, S., Wu, V., Lee, C.F., Kovalik, J., Jahoor, F. 2022. De novo glycine synthesis is reduced in adults with morbid obesity and increases following bariatric surgery. Frontiers in Endocrinology. 9(13). Article 900343. https://doi.org/10.3389/fendo.2022. 900343.
- Christiansen, L.I., Holmqvist, B., Pan, X., Holgersen, K., Lindholm, S.E., Henriksen, N.L., Burrin, D.G., Ley, D., Thymann, T., Sangild, P., Pankratova, S. 2023. Insulin-like growth factor-1 supplementation promotes brain maturation in preterm pigs. eNeuro. 10(4):1-15. https://doi.org/10. 1523/ENEURO.0430-22.2023.
- De Prisco, N., Ford, C., Elrod, N.D., Lee, W., Tang, L.C., Huang, K., Lin, A., Ji, P., Jonnakuti, V.S., Boyle, L., Cabaj, M., Botta, S., Yalamanchili, H.K. 2023. Alternative polyadenylation alters protein dosage by switching between intronic and 3'UTR sites. Science Advances. 9(7). Article eade4814. https://doi.org/10.1126/sciadv.ade4814.
- MacKay, H., Gunasekara, C.J., Yam, K., Srisai, D., Yalamanchili, H.K., Li, Y., Chen, R., Coarfa, C., Waterland, R.A. 2022. Sex-specific epigenetic development in the mouse hypothalamic arcuate nucleus pinpoints human genomic regions associated with body mass index. Science Advances. 8(39). https://doi.org/10.1126%2Fsciadv.abo3991.
- El-Ayash, H., Puyau, M., Bacha, F. 2023. Hyperglycemia: A determinant of cardiac autonomic dysfunction in youth with obesity across the spectrum of glycemic regulation. Pediatric Obesity. Article e13063. https://doi.org/10. 1111/ijpo.13063.
- Yang, L., Chen, X., Lee, C., Shi, J., Lawrence, E.B., Zhang, L., Li, Y., Gao, N., Jung, S., Creighton, C.J., Li, J., Cui, Y., Arimura, S., Lei, Y., Li, W., Shen, L. 2023. Functional characterization of age-dependent p16 epimutation reveals biological drivers and therapeutic targets for colorectal cancer. Journal of Experimental and Clinical Cancer Research. 42. Article 113. https://doi.org/10.1186/s13046-023-02689-y.
- Gencel-Augusto, J., Su, X., Qi, Y., Whitley, E.M., Pant, V., Xiong, S., Shah, V., Lin, J., Perez, E., Fiorotto, M.L., Jain, A.K., Lorenzi, P.L., Navin, N.E., Richie, E.R., Lozano, G. 2023. Dimeric p53 mutant elicits unique tumor-suppressive activities through an altered metabolic program. Cancer Discovery. 13(5):1230-1249. https://doi.org/10.1158/2159-8290.cd-22- 0872.
- Vonderohe, C., Guthrie, G., Burrin, D.G. 2023. Fibroblast growth factor 19 secretion and function in perinatal development. American Journal of Physiology - Gastrointestinal and Liver Physiology. 324(3):G190-G195. https://doi.org/10.1152/ajpgi.00208.2022.
- Bryant, K., Sandhu, J., Nguyen, J., Asonye, E., Thompson, D.J., Sisley, S. 2022. Isolation in a sea of "experts": Identifying the parental struggles caring for children with early-onset obesity. Childhood Obesity. https:// doi.org/10.1089/chi.2022.0089.
- Demello, A.S., Acorda, D.E., Thompson, D.J., Allen, D.L., Aman, R., Brandt, M.L., Sisley, S. 2022. Growing up after adolescent bariatric surgery. Clinical Nursing Research. https://doi.org/10.1177/10547738221120338.
- Bacha, F., El Ghormli, L., Braffett, B.H., Shah, A.S., Marcovina, S.M., Levitt Katz, L.E., Willi, S.M., Caprio, S., Dhaliwal, R., Gidding, S.S., for the Today Study Group. 2023. Candidate biomarkers as predictors of future kidney disease and cardiovascular dysfunction in adolescents with type 2 diabetes. Diabetes Research and Clinical Practice. 199. Article 110671. https://doi.org/10.1016/j.diabres.2023.110671.
- Trostle, A., Li, L., Kim, S., Wang, J., Al-Ouran, R., Yalamanchili, H.K., Liu, Z., Wan, Y. 2023. A comprehensive and integrative approach to MeCP2 disease transcriptomics. International Journal of Molecular Sciences. 24(6) . Article 5122. https://doi.org/10.3390/ijms24065122.
- Christiansen, L.I., Ventura, G.C., Holmqvist, B., Aasmul-Olsen, K., Lindholm, S.H., Lycas, M.D., Mori, Y., Bojsen-Møller Secher, J., Burrin, D. G., Thymann, T., Sangild, P., Pankratova, S. 2023. Insulin-like growth factor 1 supplementation supports motor coordination and affects myelination in preterm pigs. Frontiers in Neuroscience. 17. Article 1205819. https://doi.org/10.3389/fnins.2023.1205819.
- Moran, N.E., Wade, J., Stroh, R., Stoll, B., Guthrie, G., Hair, A.B., Burrin, D.G. 2023. Preterm pigs fed donor human milk have greater liver beta-carotene concentrations than pigs fed infant formula. Journal of Nutrition. https://doi.org/10.1016/j.tjnut.2023.08.026.
- Wesenberg Helt, T., Buelund, L., Borgewardt, L., Eriksen, T., Johansen, L., De Nijs, R., Holm, S., Burrin, D.G., Thymann, T., Brix Christensen, V. 2023. Towards a model of biliary atresia - pilot feasibility study in newborn piglets. Biochemistry and Biophysics Reports. 34. Article 101487. https://doi.org/10.1016/j.bbrep.2023.101487.
- Castillo Rodriguez, B., Astudillo, M., Tosur, M., Rafaey, A., McKay, S., Bacha, F., Balasubramanyam, A., Redondo, M.J. 2023. Characteristics of type 2 diabetes in female and male youth. Clinical Diabetes. 41(2):239⿿243. https://doi.org/10.2337/cd22-0057.
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Progress 10/01/21 to 09/30/22
Outputs
PROGRESS REPORT Objectives (from AD-416): We will: 1)study the effect of enteral nutrition on the downstream signaling pathways and metabolism;2)study if increased FGF19 availability controls rate of growth, tissue protein synthesis and intestinal development;3)study if being born prematurely blunts protein and glucose metabolic responses to the feeding-induced rise in amino acids and insulin; 4)identify by which amino acids, regulate protein synthesis, degradation, and accretion and how responses change with age;5)removed due to investigator departure;6)study molecular mechanisms and functional significance of differences in gene expression identified in satellite cell-derived myoblasts;7)study the impact of maternal dietary protein level during lactation;8)study if vitamin D receptors in the brain are critical for glucose regulation;9)study if leptin is involved in the regulation of gluconeogenesis via the leptin receptor and if leptin agonist and small doses of hypoglycin-A/B reduces gluconeogenesis;10) study the role of the SIRT3 in regulation of pyruvate carboxylase and the gluconeogenesis pathway;11)alter DNA methylation in specific subpopulations of hypothalamic neurons and evaluate lifelong effects on energy metabolism, food intake, and PA;12)find the causes of interindividual epigenetic variation and consequences for human energy balance;13)study the functional impact of folic acid supplementation and in intestinal carcinogenesis;14)study the effect of adiposity, adipokine dysregulation, insulin resistance and vitamin D concentrations on bone and endothelial function; 15)study the effect of vitamin D therapy on change in bone and endothelial function;16)removed due to investigator departure;17)study the CNS circuit architecture and explore circuit complexities that regulate non-homeostatic feeding behaviors via environmental signals transduced by epigenetic mechanisms;18)study the tumorigenic effects of HFCS on a humanized colon tumor mouse model;19) study the effects of HFCS on the gut microbiota of a humanized colon tumor mouse model;20)study the role of HFCS-induced gut microbiota in CRC development; create multi-omic nutritional data share portal to resolve the unmet demand for an efficient access to the large volumes of heterogeneous multi-omic data across various research labs;21)integrate heterogeneous multi-omic datasets such as genetic (SNPs), transcriptomic, epigenetic, proteomic, metabolomic and microbiome to infer molecular network structures illustrating eating disorder dynamics;&22)decode genetic and epigenetic patterns of disordered eating using machine learning methods. Approach (from AD-416): This research will be accomplished using a variety of models and scientific tools to simulate the human newborn and/or child. Researchers will use neonatal piglet and rodent models to fill these knowledge gaps. We will determine whether being born prematurely blunts the anabolic response to feeding and identify mechanisms by which amino acids, particularly leucine, regulate lean growth. Additionally we will use various rodent models to test leptin's effect on gluconeogenesis that is independent of body weight, and will utilize in vitro experiments employing primary hepatocytes. Scientists will also integrate both detailed studies of animal models and characterization of epigenetic mechanisms in humans. We will use mouse models of developmental epigenetics in the hypothalamus to understand cell type-specific epigenetic mechanisms mediating developmental programming of body weight regulation. Mouse models will also be used to investigate how folic acid intake affects epigenetic mechanisms regulating intestinal epithelial stem cell (IESC) development and characterize the involvement of these mechanisms in metabolic programming related to obesity, inflammation, and gastrointestinal cancer. In human studies, we will identify human genomic loci at which interindividual variation in DNA methylation is both sensitive to maternal nutrition in early pregnancy and associated with risk of later weight gain. We will also examine whether restoration of vitamin D sufficiency, in a randomized placebo controlled study design, has a positive effect on bone microarchitecture, bone biomarkers and endothelial function. Studies will be conducted in mice that will uncover the molecular basis of interrelationships among dietary sugar, gut microbiota, and CRC development and identify sugar-induced metabolites and/or microbes that can serve as new biomarkers and targets. Researchers will also conduct a multi-omic integrative study to systematically decipher the molecular interplay of disordered eating and neuron specific brain circuits that control feeding behavior. To review the progress made during the year, please refer to the following projects: 3092-51000-065-01S (Project #1), 3092-51000-065-02S (Project #2), 3092-51000-065-03S (Project #3) and 3092-51000-065-04S (Project #4). ACCOMPLISHMENTS 01 Vitamin D receptors in the brain are important for blood glucose regulation in males but not females. Vitamin D deficiency is associated with diabetes, but the mechanisms are unclear. We had evidence that vitamin D receptors in the paraventricular hypothalamus were important for regulating blood glucose in male mice however, we had not determined if females behaved similarly. Researchers at the Children's Nutrition Research Center in Houston, Texas, used two different mouse models in which there is a loss of the vitamin D receptor in the paraventricular hypothalamus of the brain to determine the effect in female mice. In both of our mouse models, we found that male mice that had decreased vitamin D receptors in that area of the brain had higher glucose levels than their controls, whereas female mice showed no effect of the loss of the vitamin D receptors. These findings of sex differences in mice are important to human studies investigating the role of vitamin D deficiency and overall treatment and prevention of type 2 diabetes based upon the individual's sex. 02 SIRT3 protects the heart against damaging side effects of anti-cancer drug. The chemotherapy drug Doxorubicin is used to treat breast cancer, bladder cancer, ovarian cancer, lymphoma, and leukemia and despite its benefits it may also cause damage to the heart. In searching for ways to alleviate the toxicity of Doxorubicin, researchers at the Children's Nutrition Research Center in Houston, Texas, have found that a metabolic regulating enzyme, SIRT3, offers protection against the heart impacting side-effects of Doxorubicin. We generated two mouse models with elevated heart expression of two SIRT3 isoforms, treated these mice with doxorubicin and investigated the damage to the heart using ultra-sound and other methods. We found that increased SIRT3 expression in the heart protected mice against doxorubicin-induced damage to the structure and function of the heart. SIRT3 could be a potential therapeutic target for mitigating doxorubicin-induced heart-damage. Since we have previously shown that fasting or dietary restriction increased SIRT3 expression in various tissues, fasting or dietary restriction might also mitigate the side effect of doxorubicin. 03 A dietary lipid, palmitoleic acid, suppresses liver glucose production through suppression of SIRT3. The production of glucose by the liver plays a crucial role in maintaining glucose levels during starvation however, uncontrolled glucose production by the liver contributes to elevated blood glucose in individuals with diabetes. Palmitoleic acid is a mono-unsaturated fatty acid that is available from dietary sources and exhibits beneficial effects on diabetes, inflammation, and metabolic diseases. The mechanism by which palmitoleic acid reduces blood glucose is still unclear. Researchers at the Children's Nutrition Research Center in Houston, Texas, conducted a study that revealed that palmitoleic acid reduced liver glucose production and the expression of SIRT3, a key metabolism-regulating enzyme, in high-fat diet fed mice. Overexpression of SIRT3 in the liver or in liver cells enhanced glucose synthesis, and further study revealed that SIRT3 played a role in enhancing the activities of three key enzymes involved in the synthesis of glucose. Our study uncovered the role of SIRT3 in the regulation of liver glucose production and its role in mediating the anti-diabetic effect of palmitoleic acid. These findings may help identify novel treatments of diabetes by palmitoleic acid supplementation or by inhibiting the SIRT3 enzyme. 04 The effect of cardiorespiratory fitness and insulin resistance on bone health in Hispanic children. Obesity appears to have a negative impact on pediatric bone health and insulin resistance may mediate this relationship. It is unclear if cardiorespiratory fitness may have a protective effect on bone health in obese children. Researchers at the Children's Nutrition Research Center in Houston, Texas examined data on a large number of Hispanic youths to evaluate the effect of insulin resistance and cardiorespiratory fitness on bone health. Our results showed that lean body mass is the major determinant of bone mineral content and bone mineral density in Hispanic youth. However, obesity and higher body fat have a negative effect on this relationship, while a higher fitness level was positively related to the measures of bone health. This suggests that greater cardiorespiratory fitness and higher lean mass may reduce the adverse effects of adiposity and insulin resistance on bone health in children. These findings support the importance of promoting an increase in physical activity to prevent the negative impact of obesity on bone health in children. 05 The role of sleep and eating patterns in adiposity gain among preschool- aged children. Short sleep duration (less than 9 hours in preschoolers) is related to risk for obesity in preschool children however, the underlying mechanism(s) are not clear. Researchers at the Children's Nutrition Research Center in Houston, Texas, investigated the relationship between sleep characteristics with body composition and weight-regulating behaviors in preschool-aged children (ages 3 to 5 years old). We examined the relationship between sleep, physical activity and dietary behaviors, and the effect of these behaviors on weight and fat gain a year later and found that children do not consistently meet age-recommended sleep duration. Late sleep timing was related to a delay in morning and evening meals and more caloric intake in the evening, a factor that is related to weight gain in older individuals. Both a decrease in sleep duration and later meal timing were related to fat gain a year later which indicates that insufficient sleep duration influences eating behaviors. This supports the importance of sleep hygiene with appropriate timing and adequate duration in preschool age children. 06 Energy expenditure due to gluconeogenesis in insulin resistance. Insulin resistance is a condition when cells in human muscle, fat, and liver do not respond well to insulin and are unable to easily take up glucose from the circulation of blood. For individuals with insulin resistance, suppression of glucose production from the liver by insulin is impaired, contributing to high blood glucose. Glucose production is energetically costly and may contribute to increased energy expenditure. Researchers at the Children's Nutrition Research Center in Houston, Texas, sought to determine if energy expenditure is attributable to glucose production from the liver in individuals with different types of insulin resistance conditions. We demonstrated that glucose production from the liver is a major contributor to energy expenditure in humans with insulin resistance. The findings from this study are important because they indicate that treatments for diabetes that reduce glucose production from the liver could potentially promote weight gain by decreasing the energy expenditure.
Impacts
(N/A)
Publications
- Vonderohe, C., Guthrie, G., Stoll, B., Chacko, S., Dawson, H.D., Burrin, D. G. 2021. Tissue-specific mechanisms of bile acid homeostasis and activation of FXR-FGF19 signaling in preterm and term neonatal pigs. American Journal of Physiology. https://doi.org/10.1152/ajpgi.00274.2021.
- Spooner, H., Derrick, S., Maj, M., Manjarin, R., Hernandez, G., Tailor, D., Bastani, P., Fanter, R., Fiorotto, M., Burrin, D.G., LaFrano, M., Sikalidis, A., Blank, J. 2021. High-fructose, high-fat diet alters muscle composition and fuel utilization in a juvenile Iberian pig model of non- alcoholic fatty liver disease. Nutrients. 13(12). Article 4195. https:// doi.org/10.3390/nu13124195.
- Quaye, E., Chacko, S., Chung, S.T., Brychta, R.J., Chen, K.Y., Brown, R.J. 2021. Energy expenditure due to gluconeogenesis in pathological conditions of insulin resistance. American Journal of Physiology - Endocrinology and Metabolism. 321:E795-E801. https://doi.org/10.1152/ajpendo.00281.2021.
- Puri, K., Adachi, I., Bocchini, C., Spinner, J., Denfield, S., Sisley, S., Elias, B., Jimenez-Gomez, A., Price, J., Dreyer, W., Choudhry, S., Tunuguntla, H. 2021. Trends in body mass index and association with outcomes in pediatric patients on continuous flow ventricular assist device support. ASAIO Journal. https://doi.org/10.1097/MAT. 0000000000001633.
- Guthrie, G., Vonderohe, C., Burrin, D.G. 2022. Fibroblast growth factor 15/ 19 expression, regulation, and function: An overview. Molecular and Cellular Endocrinology. 548. Article 111617. https://doi.org/10.1016/j.mce. 2022.111617.
- Dewey, K.G., Pannucci, T., Kellie, C.O., Davis, T.A., Donovan, S.M., Kleinman, R.E., Taveras, E.M., Bailey, R.L., Novotny, R., Schneeman, B.O., Stang, J., De Jesus, J., Stoody, E.E. 2021. Development of food pattern recommendations for infants and toddlers 6⿿24 months of age to support the Dietary Guidelines for Americans, 2020⿿2025. Journal of Nutrition. 151(10) :3113-3124. https://doi.org/10.1093/jn/nxab201.
- Redondo, M.J., Warnock, M.V., Libman, I.M., Bocchino, L.E., Cuthbertson, D. , Geyer, S., Pugliese, A., Steck, A.K., Evans-Molina, C., Becker, D., Sosenko, J.M., Bacha, F., and the Type 1 Diabetes TrialNet Study Group. 2021. TCF7L2 genetic variants do not influence insulin sensitivity or secretion indices in autoantibody-positive individuals at risk for type 1 diabetes. Diabetes Care. 44(9):2039-2044. https://doi.org/10.2337/dc21- 0531.
- Todd, J.N., Kleinberger, J.W., Zhang, H., Srinivasan, S., Tollefsen, S.E., Levitsky, L.L., Levitt Katz, L.E., Tryggestad, J.B., Bacha, F., Imperatore, G., Lawrence, J.M., Pihoker, C., Divers, J., Flannick, J., Dabelea, D., Florez, J.C., Pollin, T.I. 2021. Monogenic diabetes in youth with presumed type 2 diabetes: Results from the Progress in Diabetes Genetics in Youth (ProDiGY) collaboration. Diabetes Care. 44(10):2312-2319. https://doi.org/ 10.2337/dc21-0491.
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Progress 10/01/20 to 09/30/21
Outputs
PROGRESS REPORT Objectives (from AD-416): We will: 1)study the effect of enteral nutrition on the downstream signaling pathways and metabolism;2)study if increased FGF19 availability controls rate of growth, tissue protein synthesis and intestinal development;3)study if being born prematurely blunts protein and glucose metabolic responses to the feeding-induced rise in amino acids and insulin; 4)identify by which amino acids, regulate protein synthesis, degradation, and accretion and how responses change with age;5)identify the mechanisms that limit citrulline production;6)study molecular mechanisms and functional significance of differences in gene expression identified in satellite cell-derived myoblasts;7)study the impact of maternal dietary protein level during lactation;8)study if vitamin D receptors in the brain are critical for glucose regulation;9)study if leptin is involved in the regulation of gluconeogenesis via the leptin receptor and if leptin agonist and small doses of hypoglycin-A/B reduces gluconeogenesis;10)study the role of the SIRT3 in regulation of pyruvate carboxylase and the gluconeogenesis pathway;11)alter DNA methylation in specific subpopulations of hypothalamic neurons and evaluate lifelong effects on energy metabolism, food intake, and PA;12)find the causes of interindividual epigenetic variation and consequences for human energy balance;13)study the functional impact of folic acid supplementation and in intestinal carcinogenesis;14)study the effect of adiposity, adipokine dysregulation, insulin resistance and vitamin D concentrations on bone and endothelial function; 15)study the effect of vitamin D therapy on change in bone and endothelial function;16)study anthropometry and body composition, total dietary energy intake, TEE, energy balance, biomarkers of CVD health and early risk factors for T2D;17)study the CNS circuit architecture and explore circuit complexities that regulate non- homeostatic feeding behaviors via environmental signals transduced by epigenetic mechanisms;18)study the tumorigenic effects of HFCS on a humanized colon tumor mouse model;19)study the effects of HFCS on the gut microbiota of a humanized colon tumor mouse model;20)study the role of HFCS-induced gut microbiota in CRC development; create multi-omic nutritional data share portal to resolve the unmet demand for an efficient access to the large volumes of heterogeneous multi-omic data across various research labs;21)integrate heterogeneous multi-omic datasets such as genetic (SNPs), transcriptomic, epigenetic, proteomic, metabolomic and microbiome to infer molecular network structures illustrating eating disorder dynamics;&22)decode genetic and epigenetic patterns of disordered eating using machine learning methods. Approach (from AD-416): This research will be accomplished using a variety of models and scientific tools to simulate the human newborn and/or child. Researchers will use neonatal piglet and rodent models to fill these knowledge gaps. We will determine whether being born prematurely blunts the anabolic response to feeding and identify mechanisms by which amino acids, particularly leucine, regulate lean growth. Additionally we will use various rodent models to test leptin's effect on gluconeogenesis that is independent of body weight, and will utilize in vitro experiments employing primary hepatocytes. Scientists will also integrate both detailed studies of animal models and characterization of epigenetic mechanisms in humans. We will use mouse models of developmental epigenetics in the hypothalamus to understand cell type-specific epigenetic mechanisms mediating developmental programming of body weight regulation. Mouse models will also be used to investigate how folic acid intake affects epigenetic mechanisms regulating intestinal epithelial stem cell (IESC) development and characterize the involvement of these mechanisms in metabolic programming related to obesity, inflammation, and gastrointestinal cancer. In human studies, we will identify human genomic loci at which interindividual variation in DNA methylation is both sensitive to maternal nutrition in early pregnancy and associated with risk of later weight gain. We will also examine whether restoration of vitamin D sufficiency, in a randomized placebo controlled study design, has a positive effect on bone microarchitecture, bone biomarkers and endothelial function. Studies will be conducted in mice that will uncover the molecular basis of interrelationships among dietary sugar, gut microbiota, and CRC development and identify sugar-induced metabolites and/or microbes that can serve as new biomarkers and targets. Researchers will also conduct a multi-omic integrative study to systematically decipher the molecular interplay of disordered eating and neuron specific brain circuits that control feeding behavior. To review the progress made during the year, please refer to the following projects: 3092-51000-065-01S (Project #1), 3092-51000-065-02S (Project #2), 3092-51000-065-03S(Project #3) and 3092-51000-065-04S (Project #4). Record of Any Impact of Maximized Teleworking Requirement: Project 1. COVID-19 restrictions significantly limited the ability to conduct animal studies and laboratory analysis from March to November 2020. This restriction limited the ability to start new studies to process samples collected in previous animal studies. Additionally, the Children's Nutrition Research Center required that we reduce the number of mice for research by 75%. Thus, we were unable to perform the mouse studies described in the work programmed for this proposal. We are currently repopulating our mouse colony to enable the proposed studies to be performed. Depleting our breeding colony and then having to re- establish it, do the animal work and then start on the analyses requires a minimum of 12 months. We are also experiencing a staff shortage as a consequence of Baylor College of Medicine's COVID-19 freeze on recruitment and hiring of new personnel. Additionally, the availability of critical laboratory supplies and reagents necessary for the work have been delayed. We estimate that COVID-19 has delayed research progress by 9-12 months and the submission of several manuscripts by 3-6 months. Project 2. Maximized telework requirements early in this project negatively impacted the research in a variety of ways. It prevented us from performing several animal experiments. Additionally, it prevented us from conducting experiments that required close interaction between team members and direct access to different instruments. On the other hand, the maximized telework requirements forced us to shift to projects which could be done remotely and thus, publications were achieved utilizing existing datasets. Project 3. The COVID-19 pandemic has had significant negative impact on our projects. We had to substantially reduce our mouse work due to the pandemic. We have had delays with the delivery of supplies and reagents. In addition, we have experienced delays and difficulties in recruitment. Project 4. For Objectives 1 and 2, the laboratory's telework posture due to the COVID-19 pandemic hindered our capability to recruit research participants and perform clinical research studies. This led to a significant delay in achieving our milestones for the second year of the project. We have resumed our clinical research efforts gradually. We expect to be able to catch up over the next year as we ramp up research efforts. For Objective 3, telework significantly impacted our ability to recruit young school age children during the summer break. ACCOMPLISHMENTS 01 Prematurity dampens the anabolic response to nutrition. Approximately 10% of all United States infants born annually (380,000) are preterm thus it is vital to conduct studies that seek to provide optimal nutrition for this group. The lean growth of preterm infants is typically lower than infants born at term and likely contributes to undesirable short-term and long-term health outcomes. Using the neonatal pig as a model for the human infant, researchers in Houston, Texas, determined the mechanisms by which preterm birth alters the response to nutritional growth. Our work showed that preterm birth impairs the ability of skeletal muscle to increase the synthesis of protein after a meal. These studies provide vital information on the mechanisms underpinning the reduced growth of lean muscle mass after birth in preterm infants and will aid in the development of nutritional therapies to improve lean growth. 02 Creation of a new mouse model to identify vitamin D receptors in the brain. Vitamin D acts in the brain to control blood sugar, but the exact mechanisms are not known. Typically, the first step in understanding how vitamin D acts would be to determine what types of neurons contain the vitamin D receptor. However, the available antibodies to identify vitamin D receptors do not work in the brain. Researchers in Houston, Texas, created a new mouse model which identifies vitamin D receptors in the mouse brain through a special fluorescent reporter. Researchers successfully validated that only those neurons containing the fluorescent reporter were activated by vitamin D. This new mouse model is important as it allows researchers to identify and manipulate neurons containing the vitamin D receptor. This is an important new tool which will aid researchers investigating the role of vitamin D in the brain and its impact on diabetes, Alzheimer's disease, obesity, and other brain-related disorders. 03 The effect of cardiorespiratory fitness and insulin resistance on bone health in Hispanic children. Obesity appears to have a negative impact on pediatric bone health, and insulin resistance may mediate this relationship. It was unclear if cardiorespiratory fitness has a protective effect on bone in obese children thus, researchers in Houston, Texas, found that lean body mass is the major determinant of bone mineral content and bone mineral density in pubertal Hispanic youth. Increased body fat and insulin resistance were negatively related to bone mineral content. Cardiorespiratory fitness contributed positively to bone mineral content and density. This suggests that greater cardiorespiratory fitness and higher lean mass may reduce the adverse effects of adiposity and insulin resistance on bone health in children. This supports the importance of promoting physical activity to prevent the negative impact of obesity on bone health in children. 04 Metabolic flexibility across the spectrum of glycemic regulation in youth. Metabolic flexibility refers to the ability to utilize different nutrients (fats and sugars) and to transition between them while fasting and after a meal. Impairment in metabolic flexibility can lead to metabolic disease. However, it is not clear whether metabolic flexibility is impaired in obese youth, or who is at risk. Therefore, researchers in Houston, Texas, found that adolescents with prediabetes and type 2 diabetes have a defect in metabolic flexibility. Individuals with prediabetes and type 2 diabetes can't change the use of fuels as easily as normal weight individuals or individuals with obesity but with normal sugar levels. This is related to their severe insulin resistance which impairs the appropriate use of available fuels. Additional studies are needed to investigate which changes in diet or physical activity could improve how the body utilizes these nutrients. 05 Insufficient sleep duration and quality may lead to increased weight gain in children. Multiple studies have found an association between short sleep duration and obesity in children and adolescents; however, the mechanisms underlying the relationship between sleep and the risk for obesity in children are unclear. One mechanism may be through changes in energy metabolism and physical activity. Researchers in Houston, Texas, investigated the relationship of various sleep parameters (sleep duration and quality) to energy metabolism and physical activity in children and adolescents aged 5-18 years. Researchers measured the child/adolescent's body composition, basal metabolic rate, and sleep and physical activity parameters during a school break. The scientists found that children and adolescents do not consistently meet the age-recommended sleep duration during school breaks. Importantly, shorter sleep duration was associated with lower basal metabolic rate which indicates that insufficient sleep duration and late sleep timing may lead to increased weight gain over time. This supports the importance of sleep hygiene with appropriate timing and adequate duration in promoting an active lifestyle and minimizing sedentary behaviors to prevent childhood obesity. 06 Insulin resistance affects the insulin regulation of glucose and triglyceride production. Insulin resistance is a condition when cells in muscles, fat, and the liver do not respond efficiently to insulin and are unable to easily take up glucose from circulation. In the liver, insulin suppresses glucose production and increases lipid synthesis in the presence of glucose. It is not clear as to what mechanisms insulin regulates glucose and triglyceride (a type of lipid) production in humans with various types of insulin resistance conditions. Scientists in Houston, Texas, demonstrated that glycerol and free fatty acid availability (two precursors to triglyceride synthesis) are increased in two different models of insulin resistance, one involving the insulin receptor (receptor-level) and one caused by defects in the pathway after the insulin receptor (postreceptor). In receptor-level insulin resistance, free fatty acid oxidation increased glucose production rather than triglyceride production. In contrast, free fatty acids contributed to both glucose and triglyceride production in postreceptor insulin resistance conditions. The findings from this research provides details about glucose and fat metabolism in these insulin resistance conditions and insights for future research to find effective treatments. 07 Using blood markers to determine weight status in individuals with type 1 diabetes. Researchers often struggle to get accurate height and weight measurements when conducting studies outside of medical facilities. These measurements are critical for determining a person's body mass index which is used to determine if an individual is overweight or obese. Most studies obtain blood draws and there are many hormones which circulate in the blood that relate to a person's weight status; whether these hormones would be an accurate reflection of weight status in an individual with type 1 diabetes was not known. Researchers at Houston, Texas, used existing samples from a multi-site trial comprised of individuals with type 1 diabetes to determine if there were any markers identified in blood that would reflect weight status. They found that leptin was a good marker for weight status in boys but not in girls; however, waist circumference was a good marker in girls, which may be easier to collect than height and weight. Overall, this data shows promise and further studies should be performed to identify possible biomarkers since, if successful, a blood biomarker would allow for many questions related to obesity to be asked in existing datasets of banked samples. 08 Leptin decreases fat synthesis in individuals with lipodystrophy. Lipodystrophy is a medical condition in which the body has abnormal distribution of fat and results in nonalcoholic fatty liver disease, the most common cause of chronic liver disease in the U.S. and is likely to become the leading cause of liver failure. It is not known if a leptin analog treatment in individuals with lipodystrophy would reduce fat synthesis in the liver. Scientists in Houston, Texas, demonstrated that six months of the leptin analog (metreleptin) treatment in very insulin-resistant people with lipodystrophy led to near normalization of fatty acid synthesis. Improvements in fat synthesis in the liver were associated with reductions in blood glucose and improved insulin sensitivity. These findings indicate that metreleptin treatment lowered liver fat accumulation (hepatic steatosis) and blood lipid levels and suggests that treatments targeting multiorgan insulin resistance may improve nonalcoholic fatty liver disease.
Impacts
(N/A)
Publications
- Ettayebi, K., Tenge, V., Cortes-Penfield, N., Crawford, S., Neill, F., Zeng, X., Yo, X., Ayyar, V., Burrin, D.G., Ramani, S., Atmar, R., Estes, M. 2021. New insights and enhanced human norovirus cultivation in human intestinal enteroids. American Society for Microbiology. 6(1):e01136-20. https://doi.org/10.1128/mSphere.01136-20.
- Liu, H., He, Y., Beck, J., Da Silva Teixeira, S., Harrison, K., Xu, Y., Sisley, S. 2020. Defining vitamin D receptor expression in the brain using a novel VDRCre mouse. Journal of Comparative Neurology. https://doi.org/10. 1002/cne.25100.
- Cade, T.W., Bohnert, K.L., Bittel, A.J., Chacko, S.J., Patterson, B.W., Pacak, C.A., Byrne, B.J., Vernon, H.J., Reeds, D.N. 2020. Arginine kinetics are altered in a pilot sample of adolescents and young adults with Barth syndrome. Molecular Genetics and Metabolism. 25:100675. https:// doi.org/10.1016/j.ymgmr.2020.100675.
- Guthrie, G., Burrin, D.G. 2021. Impact of parenteral lipid emulsion components on cholestatic liver disease in neonates. Nutrients. 13(2):508. https://doi.org/10.3390/nu13020508.
- Leroy, J.L., Frongillo, E.A., Dewan, P., Black, M.M., Waterland, R.A. 2020. Can children catch up from the consequences of undernourishment? Evidence from child linear growth, developmental epigenetics, and brain and neurocognitive development. Advances in Nutrition. 11(4):1032-1041. https:/ /doi.org/10.1093/advances/nmaa020.
- Burrin, D.G., Marini, J., Premkumar, M., Stoll, B., Sangild, P. 2021. Advancements in research on necrotizing enterocolitis pathogenesis and prevention using pigs. In: Hackam, D.J. editor. Necrotizing Enterocolitis: Pathogenesis, Diagnosis and Treatment. 1st edition. Boca Raton, FL: CRC Press. p.220-232. https://doi.org/10.1201/9780429288302.
- Mohammad, M., Didelija, I., Stoll, B., Nguyen, T., Marini, J. 2021. Pegylated arginine deiminase depletes plasma arginine but maintains tissue arginine availability in young pigs. American Journal of Physiology. 320(3) :E641-E652. https://doi.org/10.1152/ajpendo.00472.2020.
- Kim, J.Y., Tfayli, H., Bacha, F., Arslanian, S. 2021. The shape of the oral glucose tolerance test-glucose response curve in islet cell antibody- positive vs. -negative obese youth clinically diagnosed with type 2 diabetes. Journal of Obesity. https://doi.org/10.7570/jomes20088.
- Deng, F., Zhou, H., Lin, Y., Heim, J.A., Shen, L., Li, Y., Zhang, L. 2021. Predict multicategory causes of death in lung cancer patients using clinicopathologic factors. Computers in Biology and Medicine. 129:104161. https://doi.org/10.1016/j.compbiomed.2020.104161.
- Kim, J., Tfayli, H., Bacha, F., Lee, S., Gebara, N., Arslanian, S. 2020. B- cell impairment and clinically meaningful alterations in glycemia in obese youth across the glucose tolerance spectrum. Metabolism: Clinical and Experimental. 112:154346. https://doi.org/10.1016/j.metabol.2020.154346.
- Robinson, S.L., Zeng, X., Guan, W., Sundaram, R., Mendola, P., Putkick, D. L., Waterland, R.A., Ganasekara, C., Kannan, K., Gao, C., Bell, E., Yeung, E.H. 2021. Perfluorooctanoic acid (PFOA) or perfluorooctane sulfonate (PFOS) and DNA methylation in newborn dried blood spots in the upstate KIDS cohort. Environmental Research. 194:110668. https://doi.org/10.1016/j. envres.2020.110668.
- Scott, A.C., Duryea, J.D., MacKay, H., Baker, M.S., Laritsky, E., Gunasekara, C.J., Coarfa, C., Waterland, R.A. 2020. Identification of cell type-specific methylation signals in bulk whole genome bisulfite sequencing data. Genome Biology. 21(1):156. https://doi.org/10.1186/s13059- 020-02065-5.
- Mukherjee, S., Mo, J., Paolella, L.M., Perry, C.E., Toth, J., Hugo, M.M., Chu, Q., Tong, Q., Chellappa, K., Baur, J.A. 2021. SIRT3 is required for liver regeneration but not for the beneficial effect of nicotinamide riboside. Journal of Clinical Immunology Insights (JCI Insights). 6(7) :E147193. https://doi.org/10.1172/jci.insight.147193.
- Shen, H., Holliday, M., Sheikh-Hamad, D., Li, Q., Tong, Q., David Hamad, C. , Pan, J.S. 2021. Sirtuin-3 mediates sex differences in kidney ischemia- reperfusion injury. Translational Research. https://doi.org/10.1016/j.trsl. 2021.03.015.
- Deng, F., Shen, L., Wang, H., Zhang, L. 2020. Classify multicategory outcome in patients with lung adenocarcinoma using clinical, transcriptomic and clinico-transcriptomic data: Machine learning versus multinomial models. American Journal of Cancer Research. 10(12):4624-4639.
- Al-Gadi, I., Sisley, S. 2021. Case-based curriculum for pediatric residents in diabetes fundamentals. MedEdPORTAL. 17:11157. https://doi.org/ 10.15766/mep_2374-8265.11157.
- Bailey, R.L., Ard, J.D., Davis, T.A., Naimi, T.S., Schneeman, B.O., Stang, J.S., Dewey, K.G., Donovan, S.M., Novotny, R., Snetselaar, L.G. 2021. A proposed framework for identifying nutrients and food components of public health relevance in the Dietary Guidelines for Americans. Journal of Nutrition. 151(5):1197-1204. https://doi.org/10.1093/jn/nxaa459.
- El-Kadi, S.W., Boutry-Regard, C., Suryawan, A., Nguyen, H.V., Kimball, S.R. , Fiorotto, M.L., Davis, T.A. 2020. Intermittent bolus feeding enhances organ growth more than continuous feeding in a neonatal piglet model. Current Developments in Nutrition. 4(12):nzaa170. https://doi.org/10.1093/ cdn/nzaa170.
- Bacha, F., Bartz, S.K., Puyau, M., Adolph, A., Sharma, S. 2021. Metabolic flexibility across the spectrum of glycemic regulation in youth. Journal of Clinical Investigation. 6(4):e146000. https://doi.org/10.1172/jci. insight.146000.
- Jindal, I., Puyau, M., Adolph, A., Butte, N., Musaad, S., Bacha, F. 2020. The relationship of sleep duration and quality to energy expenditure and physical activity in children. Pediatric Obesity. e12751. https://doi.org/ 10.1111/ijpo.12751.
- Baykal, A.P., Parks, E.J., Shamburek, R., Syed-Abdul, M.M., Chacko, S., Cochran, E., Startzell, M., Gharib, A.M., Ouwerkerk, R., Abd-Elmoniem, K.Z. , Walter, P.J., Muniyappa, R., Chung, S.T., Brown, R.J. 2020. Leptin decreases de novo lipogenesis in patients with lipodystrophy. Journal of Clinical Investigation. 5(14):e137180. https://doi.org/10.1172/jci.insight. 137180.
- Maj, M., Harbottle, B., Thomas, P., Hernandez, G., Smith, V., Edwards, M., Fanter, R., Glanz, H., Immoos, C., Burrin, D.G., Santiago-Rodriguez, T., La Franco, M., Manjarin, R. 2021. Consumption of high-fructose corn syrup compared with sucrose promotes adiposity and increased triglyceridemia but comparable NAFLD severity in juvenile Iberian pigs. Journal of Nutrition. 151(5):1139-1149. https://doi.org/10.1093/jn/nxaa441.
- Guthrie, G., Stoll, B., Chacko, S., Mohammad, M., Style, C., Verla, M., Olutoye, O., Schady, D., Lauridsen, C., Tataryn, N., Burrin, D.G. 2021. Depletion and enrichment of phytosterols in soybean oil lipid emulsions directly associate with serum markers of cholestasis in preterm PN-fed pigs. Journal of Parenteral and Enteral Nutrition. https://doi.org/10.1002/ jpen.2088.
- Kumar, P., Liu, C., Suliburk, J.W., Minard, C.G., Muthupillai, R., Chacko, S., Hsu, J.W., Jahoor, F., Sekhar, R.V. 2020. Supplementing glycine and n- acetylcysteine (GlyNAC) in aging HIV patients improves oxidative stress, mitochondrial dysfunction, inflammation, endothelial dysfunction, insulin resistance, genotoxicity, strength, and cognition: Results of an open- label clinical trial. Biomedicines. 8(10):390. https://doi.org/10.3390/ biomedicines8100390.
- Zeltser, N., Meyer, I., Hernandez, G., Trahan, M., Fanter, R., Abo-Ismail, M., Glanz, H., Strand, C., Burrin, D.G., La Frano, M., Manjarin, R., Maj, M. 2020. Neurodegeneration in juvenile Iberian pigs with diet-induced nonalcoholic fatty liver disease. American Journal of Physiology - Endocrinology and Metabolism. 319(3):E592-E606. https://doi.org/10.1152/ ajpendo.00120.2020.
- Suryawan, A., El-Kadi, S.W., Nguyen, H.V., Fiorotto, M.L., Davis, T.A. 2021. Intermittent bolus compared with continuous feeding enhances insulin and amino acid signaling to translation initiation in skeletal muscle of neonatal pigs. Journal of Nutrition. https://doi.org/10.1093/jn/nxab190.
- Rudar, M., Naberhuis, J.K., Suryawan, A., Nguyen, H.V., Stoll, B., Style, C.C., Verla, M.A., Olutoye, O.O., Burrin, D.G., Fiorotto, M.L. 2021. Prematurity blunts the insulin- and amino acid-induced stimulation of translation initiation and protein synthesis in skeletal muscle of neonatal pigs. American Journal of Physiology - Endocrinology and Metabolism. 320(3):E551⿿E565. https://doi.org/10.1152/ajpendo.00203.2020.
- Sorkin, J.D., Manary, M., Smeets, P.A., MacFarlane, A.J., Astrup, A., Duggan, C.P., Hogans, B.B., Odle, J., Davis, T.A., Tucker, K.L. 2021. A guide for authors and readers of the American Society for Nutrition Journals on the proper use of P values and strategies that promote transparency and improve research reproducibility. American Journal of Clinical Nutrition. https://doi.org/10.1093/ajcn/nqab223.
- Gooding, H.C., Gidding, S.S., Moran, A.E., Redmond, N., Allen, N.B., Bacha, F., Burns, T.L., Catov, J.M., Grandner, M.A., Mullan Harris, K., Johnson, H.M., Kiernan, M., Lewis, T.T., Matthews, K.A., Monaghan, M., Robinson, J. G., Tate, D., Bibbins-Domingo, K., Spring, B. 2020. Challenges and opportunities for the prevention and treatment of cardiovascular disease among young adults: Report from a National Heart, Lung, and Blood Institute working group. Journal of the American Heart Association. 9(19) :e016115. https://doi.org/10.1161/JAHA.120.016115.
- Sekizkardes, H., Chung, S.T., Chacko, S., Haymond, M.W., Startzell, M., Walter, M., Walter, P.J., Lightbourne, M., Brown, R.J. 2020. Free fatty acid processing diverges in human pathologic insulin resistance conditions. Journal of Clinical Investigation. 130(7):3592-3602. https://doi.org/10. 1172/JCI135431.
- Momin, S.R., Senn, M.K., Buckley, S., Buist, N.R., Gandhi, M., Hair, A.B., Hughes, S.O., Hodges, K.R., Lange, W.C., Papaioannou, M.A., Phan, M., Waterland, R.A., Wood, A.C. 2020. Rationale and design of the Baylor Infant Twin Study (BITS) - A study assessing obesity-related risk factors from infancy. Obesity Science & Practice. https://doi.org/10.1002/osp4.463.
- Redondo, M., Siller, A., Gu, X., Tosur, M., Bondy, M., Devaraj, S., Sisley, S. 2020. Sex differences in circulating leptin as a marker of adiposity in obese or overweight adolescents with type 1 diabetes. BMJ Open Diabetes Research & Care. https://doi.org/10.1136/bmjdrc-2020-001683.
- Yakah, W., Singh, P., Brown, J., Stoll, B., Burrin, D.G., Premkumar, M., Otu, H., Gu, X., Dillon, S., Liberman, T., Freedman, S., Martin, C. 2020. Parenteral lipid emulsions induce unique ileal fatty acid and metabolomic profiles but do not increase the risk of necrotizing enterocolitis in preterm pigs. American Journal of Physiology - Gastrointestinal and Liver Physiology. https://doi.org/10.1152/ajpgi.00311.2020.
- Mohammad, M.A., Didelija, I.C., Marini, J.C. 2020. Arginase II plays a central role in the sexual dimorphism of arginine metabolism in C57BL/6 mice. Journal of Nutrition. 150(12):3133-3140. https://doi.org/10.1093/jn/ nxaa318.
- Mohammad, M., Didelija, I., Stoll, B., Burrin, D.G., Marini, J. 2020. Modeling age-dependent developmental changes in the expression of genes involved in citrulline synthesis using pig enteroids. Physiological Reports. 8(21):e14565. https://doi.org/10.14814/phy2.14565.
- Yakah, W., Ramiro-Cortijo, D., Singh, P., Brown, J., Stoll, B., Kulkarni, M., Oosterloo, B., Burrin, D.G., Maddipati, K., Fichorova, R., Freedman, S. , Martin, C. 2021. Parenteral fish-oil containing lipid emulsions limit initial lipopolysaccharide-induced host immune responses in preterm pigs. Nutrients. 13(1):25. https://doi.org/10.3390/nu13010205.
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Progress 10/01/19 to 09/30/20
Outputs
Progress Report Objectives (from AD-416): Our goal is to identify strategies to optimize the nutrition and health of infants and their development. We will: 1) determine the effect of enteral nutrition on the downstream signaling pathways and metabolism in various tissues; 2) determine if increased FGF19 availability controls the rate of growth, tissue protein synthesis and intestinal development; 3) determine if being born prematurely blunts protein and glucose metabolic responses to the feeding-induced rise in amino acids and insulin; 4) identify by which amino acids, regulate protein synthesis, degradation, and accretion and how these responses change with age; 5) identify the mechanisms that limit citrulline production; determine the basis for the greater citrulline production observed in females and determine the utilization of citrulline for endogenous arginine synthesis at different stages; 6) study the molecular mechanisms and functional significance of differences in gene expression identified in satellite cell-derived myoblasts; 7) determine the impact of maternal dietary protein level during lactation; 8) determine if vitamin D receptors in the brain are critical for glucose regulation; 9) determine if leptin is involved in the regulation of gluconeogenesis via the leptin receptor and if leptin agonist and small doses of hypoglycin-A or B reduces the rates of gluconeogenesis; 10) study the role of the SIRT3 in regulation of pyruvate carboxylase and the gluconeogenesis pathway; 11) alter DNA methylation in specific subpopulations of hypothalamic neurons and evaluate lifelong effects on energy metabolism, food intake, and physical activity; isolate specific neuronal (and potentially non-neuronal) hypothalamic cell types to evaluate cell type-specific alterations in DNA methylation in established models of nutritional programming; 12) find the causes of interindividual epigenetic variation and consequences for human energy balance; identify human metastable epialleles that predict risk of obesity; assess how DNA methylation at obesity-associated metastable epialleles is affected by maternal periconceptional nutrition; 13) determine the functional impact of folic acid supplementation and in intestinal carcinogenesis; 14) study the effect of adiposity, adipokine dysregulation, insulin resistance and vitamin D concentrations on bone microarchitecture, bone biomarkers and endothelial function; 15) evaluate the effect of high dose vitamin D therapy on change in bone microarchitecture, restoration of bone biomarkers balance and endothelial function; and 16) determine anthropometry and body composition, total dietary energy intake, total energy expenditure, energy balance, biomarkers of cardiovascular health and early risk factors for Type 2 diabetes. Approach (from AD-416): This research will be accomplished using a variety of models and scientific tools to simulate the human newborn and/or child. Researchers will use neonatal piglet and rodent models to fill these knowledge gaps. We will determine whether being born prematurely blunts the anabolic response to feeding and identify mechanisms by which amino acids, particularly leucine, regulate lean growth. Additionally we will use various rodent models to test leptin's effect on gluconeogenesis that is independent of body weight, and will utilize in vitro experiments employing primary hepatocytes. Scientists will also integrate both detailed studies of animal models and characterization of epigenetic mechanisms in humans. We will use mouse models of developmental epigenetics in the hypothalamus to understand cell type-specific epigenetic mechanisms mediating developmental programming of body weight regulation. Mouse models will also be used to investigate how folic acid intake affects epigenetic mechanisms regulating intestinal epithelial stem cell (IESC) development and characterize the involvement of these mechanisms in metabolic programming related to obesity, inflammation, and gastrointestinal cancer. In human studies, we will identify human genomic loci at which interindividual variation in DNA methylation is both sensitive to maternal nutrition in early pregnancy and associated with risk of later weight gain. We will also examine whether restoration of vitamin D sufficiency, in a randomized placebo controlled study design, has a positive effect on bone microarchitecture, bone biomarkers and endothelial function. To review the progress made during the year, please refer to the following projects: 3092-51000-065-01S (Project #1), 3092-51000-065-02S (Project #2), 3092-51000-065-03S (Project #3) and 3092-51000-065-04S (Project #4). Accomplishments 01 Prematurity blunts the synthesis of muscle proteins after a meal. Worldwide, approximately 15 million infants are born preterm and these infants typically have a lower lean mass than those born full term. The lower lean mass in premature infants may contribute to their poorer short- and long-term health outcomes. Using the neonatal piglet as a model for the human infant, researchers in Houston, Texas, conducted a study to determine if preterm birth alters the intracellular mechanisms that regulate muscle growth in response to feeding. We showed that the synthesis of proteins in muscle after a meal was lower in preterms than those born at term, leading to a reduction in growth. This reduced response in the preterms can be attributed to a blunting of the activation of the intracellular signaling pathways in muscle that are regulated by amino acids and insulin in the blood. These animal studies provide the mechanisms that underlie the reduced lean growth in premature births and may provide relevance for the bedside care of preterm infants. 02 New generation lipid emulsions prevent liver disease. In the U.S., the main lipid emulsion approved for use in total parenteral nutrition (TPN) for preterm infants is based on soybean oil, called Intralipid. Studies in preterm babies and our studies in preterm piglets have shown that long-term infusion of soybean emulsions leads to a life- threatening condition known as parenteral nutrition-associated liver disease (PNALD). Researchers in Houston, Texas, tested two new lipid emulsions in premature, newborn piglets. One group received the new emulsion containing four different fats, called SMOF, and a second group (EXP) got a similar emulsion, but with enriched levels of key omega-fatty acids that are important for immune function. Our results showed that the SMOF and EXP emulsions prevented PNALD when compared to a control group given Intralipid. We also found that these new emulsions maintained the normal flow of bile into the gut and this led to marked changes in the gut bacterial population. These findings confirm previous work and show that new generation lipid emulsions prevent liver disease and that the underlying explanation may be related to changes in the bacteria in the gut. 03 Resources for pediatricians who provide care for obese children. When caring for obese children, pediatric health care providers must be able to gather information on diet, sleep, TV time, exercise, family history, as well as other items during a short visit and offer recommendations. There are few concise resources to help providers gather and evaluate information; thus, researchers at Houston, Texas, reviewed the literature for pediatric obesity and published a concise curation of resources for pediatric providers to aid families with information on nutrition, time-constraint strategies, and harmful eating behaviors. This work will be useful to all pediatric healthcare providers who counsel families with obese children. 04 Vitamin D enhances insulin action in brain cells. Vitamin D is associated with type 2 diabetes, but mechanisms understanding why are not clear. Researchers in Houston, Texas, previously showed that the brain may be a key site for vitamin D action to regulate blood sugar levels. New research shows that in brain cells, vitamin D increases the ability of insulin to act within these cells. Additionally, this new research shows that a key insulin pathway, the PI3K pathway, was needed in order for vitamin D to have both rapid and long-acting effects in brain cells. This is significant because it gives further evidence of how vitamin D may act in the brain to regulate blood sugar levels and demonstrates that the vitamin D and insulin pathways are interdependent in the brain. 05 Impaired suppression of glucose production in lean type 2 diabetic condition. Most investigations about type 2 diabetes have focused on the obese population; however, there is a distinct sub-population of type 2 diabetes patients who are lean with normal body mass index. It is not known if glucose production by the liver is differently affected in these individuals. Scientists in Houston, Texas, using a lean type 2 diabetes rat model, demonstrated that glucose production from the liver did not decrease appropriately after animals had eaten. These findings provide insights for future research about how to achieve better blood glucose control among this distinct sub-population of type 2 diabetes patients who are lean with normal body mass index. 06 Metabolic abnormalities in children, adolescents and young adults with Barth syndrome. Barth syndrome is a rare metabolic and neuromuscular disorder that occurs primarily in males with mortality frequently occurring during infancy and adolescence due to factors associated with the heart, immune system, muscles, and overall growth. It is not known if fatty acid and glucose metabolism is altered during this condition in humans. Researchers in Houston, Texas, demonstrated that fat oxidation was severely blunted during exercise in children, and an inability to increase fat metabolism during moderate physical activity is partially compensated by elevations in glucose metabolism. The data from this study suggests that abnormalities in glucose and fat metabolism contribute to the Barth syndrome condition and this research provides insights and potential nutritional interventions for the treatment of this condition. 07 Blood sugar pattern can inform risk for diabetes in children. It is important to identify children who are at risk for diabetes as early as possible, as some children do not receive a diagnosis until their symptoms are severe. A means to determine diabetes risk is to measure one's blood sugar (glucose) after consuming a sugary drink, and how quickly the blood sugar level rises. Researchers in Houston, Texas, along with collaborators from the University of Pittsburgh investigated whether the time for glucose to reach a peak after a sugary drink is associated with levels of insulin, a hormone that is important to keep the blood sugars normal. Individuals with a "late-peak" in blood sugar levels had lower insulin production and were less responsive to insulin. These findings indicate that examining how quickly the sugar rises after a sugary drink can inform pediatricians about a child's risk for diabetes and provide for an early intervention.
Impacts
(N/A)
Publications
- Suryawan, A.A., Rudar, M., Fiorotto, M.L., Davis, T.A. 2020. Differential regulation of mTORC1 activation by leucine and beta-hydroxy-beta- methylbutyrate in skeletal muscle of neonatal pigs. Journal of Applied Physiology. 128(2):286-295.
- Ahnfeldt, A., Baek, O., Hui, Y., Nielsen, C., Obelitz-Ryom, K., Busk- Anderson, T., Ruge, A., Holst, J., Rudloff, S., Burrin, D.G., Nguyen, D., Nielsen, D., Zachariassen, G., Bering, S., Thymann, T., Sangild, P. 2020. Nutrient restriction has limited short-term effects on gut, immunity, and brain development in preterm pigs. Journal of Nutrition.
- Mohammad, M., Didelija, I., Wang, X., Stoll, B., Burrin, D.G., Marini, J. 2019. Developmental changes in the utilization of citrulline by neonatal pigs. American Journal of Physiology - Renal Physiology.
- Hernandez, G.V., Smith, V.A., Melynk, M., Burd, M.A., Sprayberry, K.A., Edwards, M.S., Peterson, D.G., Bennet, D.C., Fanter, R.K., Columbus, D.A., Steibel, J., Glanz, H., Immoos, C., Rice, M.S., Santiago-Rodriguez, T.M., Blank, J.M., Vanderkelen, J.J., Kitts, C.L., Piccolo, B.D., La Frano, M.R., Burrin, D.G., Maj, M., Manjarin, R. 2020. Dysregulated FXR-FGF19 signaling and choline metabolism is associated with gut dysbiosis and hyperplasia in a novel pig model of pediatric NASH. American Journal of Physiology - Gastrointestinal and Liver Physiology. 318(3):G582-G609.
- Smith, V., Jiang, Y., Thymann, T., Sangild, P., Maj, M., Manjarin, R., Burrin, D.G. 2020. Rapid postnatal upregulation of intestinal FXR-FGF19 signalling in premature pigs. Journal of Pediatric Gastroenterology and Nutrition.
- Naberhuis, J.K., Suryawan, A., Nguyen, H.V., Hernandez-Garcia, A., Cruz, S. M., Lau, P.E., Olutoye, O.O., Stoll, B., Burrin, D.G., Fiorotto, M.L., Davis, T.A. 2019. Prematurity blunts the feeding-induced stimulation of translation initiation signaling and protein synthesis in muscle of neonatal piglets. American Journal of Physiology.
- Burrin, D.G., Sangild, P., Stoll, B., Thymann, T., Buddington, R., Marini, J., Olutoye, O., Shulman, R. 2020. Translational advances in pediatric nutrition and gastroenterology: New insights from pig models. Annual Review of Animal Biosciences. 8(321):354.
- Zachery, M., Sisley, S. 2020. The pediatric obesity encounter: Literature and resources to help with 4 common issues. Current Nutrition Reports. 9:94�100.
- Blesson, C., Schutt, A., Chacko, S., Marini, J.C., Mathew, P.R., Tanchico, D., Balakrishnan, M., Yallampalli, C. 2019. Sex dependent dysregulation of hepatic glucose production in lean type 2 diabetic rats. Frontiers in Endocrinology. 10:538.
- Nielsen, C., Hui, Y., Nguyen, D., Ahnfeldt, A., Burrin, D.G., Hartmann, B., Heckmann, A., Sangild, P., Thymann, T., Berinf, S. 2020. Alpha- lactalbumin enriched whey protein concentrate to improve gut, immunity and brain development in preterm pigs. Nutrients. 12(1):245.
- The Cancer Research UK - Ludwig Cancer Research Nutrition and Cancer Prevention Collaborative Group. 2019. Current opportunities to catalyze research in nutrition and cancer prevention - An interdisciplinary perspective. BioMed Central (BMC) Medicine. 17:148.
- Li, G., Petkova, T.D., Laritsky, E., Kessler, N., Baker, M.S., Zhu, S., Waterland, R.A. 2019. Early postnatal overnutrition accelerates aging- associated epigenetic drift in pancreatic islets. Environmental Epigenetics. 5(3):dvz015.
- Teixeira, S., Harrison, K., Uzodike, M., Rajapakshe, K., Coarfa, C., He, Y. , Xu, Y., Sisley, S. 2020. Vitamin D actions in neurons require the PI3K pathway for both enhancing insulin signaling and rapid depolarizing effects. The Journal of Steroid Biochemistry and Molecular Biology. 200:105690.
- Zang, T., Liu, J., Tong, Q., Lin, L. 2020. SIRT3 acts as a positive autophagy regulator to promote lipid mobilization in adipocytes via activating AMPK. International Journal of Molecular Sciences. 21(2):372.
- Xin, L., Yang, L., Mao, Z., Pan, X., Zhao, Y., Gu, X., Eckel-Mahan, K., Zuo, Z., Tong, Q., Hartig, S.M., Cheng, X., Du, G., Moore, D.D., Bellen, H. J., Sesaki, H., Sun, K. 2020. Novel role of dynamin-related-protein 1 in dynamics of ER-lipid droplets in adipose tissue. Federation of American Societies for Experimental Biology Conference.
- Horne, V., Bielamowicz, K., Nguyen, J., Hilsenbeck, S., Holly, L., Sonabend, R., Wood, A., Okcu, F., Sisley, S. 2020. Methylphenidate improves weight control in childhood brain tumor survivors with hypothalamic obesity. Pediatric Blood and Cancer. e28379.
- Kim, J.Y., Tfayli, H., Bacha, F., Lee, S., Michaliszyn, S.F., Yousuf, S., Gebara, N., Arslanian, S. 2019. B-cell function, incretin response, and insulin sensitivity of glucose and fat metabolism in obese youth: Relationship of OGTT-time-to-glucose-peak. Pediatric Diabetes. 21:18-27.
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Progress 10/01/18 to 09/30/19
Outputs
Progress Report Objectives (from AD-416): Our goal is to identify strategies to optimize the nutrition and health of infants and their development. We will: 1) determine the effect of enteral nutrition on the downstream signaling pathways and metabolism in various tissues; 2) determine if increased FGF19 availability controls the rate of growth, tissue protein synthesis and intestinal development; 3) determine if being born prematurely blunts protein and glucose metabolic responses to the feeding-induced rise in amino acids and insulin; 4) identify by which amino acids, regulate protein synthesis, degradation, and accretion and how these responses change with age; 5) identify the mechanisms that limit citrulline production; determine the basis for the greater citrulline production observed in females and determine the utilization of citrulline for endogenous arginine synthesis at different stages; 6) study the molecular mechanisms and functional significance of differences in gene expression identified in satellite cell-derived myoblasts; 7) determine the impact of maternal dietary protein level during lactation; 8) determine if vitamin D receptors in the brain are critical for glucose regulation; 9) determine if leptin is involved in the regulation of gluconeogenesis via the leptin receptor and if leptin agonist and small doses of hypoglycin-A or B reduces the rates of gluconeogenesis; 10) study the role of the SIRT3 in regulation of pyruvate carboxylase and the gluconeogenesis pathway; 11) alter DNA methylation in specific subpopulations of hypothalamic neurons and evaluate lifelong effects on energy metabolism, food intake, and physical activity; isolate specific neuronal (and potentially non-neuronal) hypothalamic cell types to evaluate cell type-specific alterations in DNA methylation in established models of nutritional programming; 12) find the causes of interindividual epigenetic variation and consequences for human energy balance; identify human metastable epialleles that predict risk of obesity; assess how DNA methylation at obesity-associated metastable epialleles is affected by maternal periconceptional nutrition; 13) determine the functional impact of folic acid supplementation and in intestinal carcinogenesis; 14) study the effect of adiposity, adipokine dysregulation, insulin resistance and vitamin D concentrations on bone microarchitecture, bone biomarkers and endothelial function; 15) evaluate the effect of high dose vitamin D therapy on change in bone microarchitecture, restoration of bone biomarkers balance and endothelial function; and 16) determine anthropometry and body composition, total dietary energy intake, total energy expenditure, energy balance, biomarkers of cardiovascular health and early risk factors for Type 2 diabetes. Approach (from AD-416): This research will be accomplished using a variety of models and scientific tools to simulate the human newborn and/or child. Researchers will use neonatal piglet and rodent models to fill these knowledge gaps. We will determine whether being born prematurely blunts the anabolic response to feeding and identify mechanisms by which amino acids, particularly leucine, regulate lean growth. Additionally we will use various rodent models to test leptin's effect on gluconeogenesis that is independent of body weight, and will utilize in vitro experiments employing primary hepatocytes. Scientists will also integrate both detailed studies of animal models and characterization of epigenetic mechanisms in humans. We will use mouse models of developmental epigenetics in the hypothalamus to understand cell type-specific epigenetic mechanisms mediating developmental programming of body weight regulation. Mouse models will also be used to investigate how folic acid intake affects epigenetic mechanisms regulating intestinal epithelial stem cell (IESC) development and characterize the involvement of these mechanisms in metabolic programming related to obesity, inflammation, and gastrointestinal cancer. In human studies, we will identify human genomic loci at which interindividual variation in DNA methylation is both sensitive to maternal nutrition in early pregnancy and associated with risk of later weight gain. We will also examine whether restoration of vitamin D sufficiency, in a randomized placebo controlled study design, has a positive effect on bone microarchitecture, bone biomarkers and endothelial function. To review the progress made during the year, please refer to the following projects: 3092-51000-065-01S (Project #1), 3092-51000-065-02S (Project #2) , and 3092-51000-065-03S (Project #3).
Impacts
(N/A)
Publications
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